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1. Dual diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly

Author: Ekaterina Lyulcheva-Bennett, Christopher Kershaw, Eleanor Baker, Stuart Gillies, Emma McCarthy, Jenny Higgs, Natalie Canham, Dawn Hennigan, Chris Parks, and Daimark Bennett
Subjects: Achondroplasia, Mandibulofacial dysostosis with microcephaly, Dual molecular diagnosis, Whole genome sequencing, Deep phenotyping, Blended phenotype, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient’s symptoms, opening new avenues for diagnosis and management. Case Presentation We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). Conclusion This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.
Published: 2024
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2. Implementation of a national rapid prenatal exome sequencing service in England: evaluation of service outcomes and factors associated with regional variation

Author: Rema Ramakrishnan, Corinne Mallinson, Steven Hardy, Jennifer Broughan, Maisie Blyth, Gabriella Melis, Catherine Franklin, Melissa Hill, Rhiannon Mellis, Wing Han Wu, Stephanie Allen, Lyn S. Chitty, Marian Knight, EXPRESS Clinical Outcomes Group, Ruth Armstrong, Tazeen Ashraf, Ana Beleza-Meireles, Marta Bertoli, Lucy Bownass, Jennifer Campbell, Natalie Canham, Ruth Cleaver, Jan Cobben, Jacqueline Eason, Nour Elkhateeb, Alice Gardham, Alice Garrett, Sara Hillman, Emma Hobson, Simon Holden, Muriel Holder-Espinasse, Tessa Homfray, Monika Kosicka-Slawinska, Alison Male, Sahar Mansour, Sarju G. Mehta, Cathryn Moss, Jessica Myring, Pranav Pandya, Katrina Prescott, Lorna Randall, Sarah Richardson, Alexander Ross, Alison Stewart, Dagmar Tapon, Hannah Titheradge, Pradeep Vasudevan, Astrid Weber, and Louise Wilson
Subjects: prenatal, exome sequencing, structural defects, genetic diagnosis, implementation, Genetics, QH426-470
Abstract: IntroductionPrenatal exome sequencing (pES) can enhance genetic diagnosis of fetuses with structural anomalies and has recently been introduced as a national service in England. We aimed to examine service outcomes such as diagnostic yield (definite final diagnosis), referral rate, and sources of referral, and explore variation in outcomes of pES by individual or service level factors between 01 October 2021 and 30 June 2022.MethodspES testing results from the National Health Service laboratories performing testing were linked to National Congenital Anomaly and Rare Disease Registration Service data and the Maternity Services Data Set and descriptive statistics computed.ResultsThere were 475,089 women who gave birth in England during the study period. The referral rate for pES was 8.6 (95% CI 7.8, 9.4) per 10,000 maternities. About 59% of those referred proceeded with pES testing and 35% of women who proceeded received a definite final diagnosis with a median turnaround time of 15 days. Of those who had pES testing, 64.6% had a live birth, 25.3% underwent termination of pregnancy (median gestational age at termination: 26 weeks), and 9.3% had a stillbirth. Among the 85 women who had a definite final diagnosis, 40% had a termination of pregnancy, 18% had a stillbirth, and 42% had a live birth. The corresponding figures among women without a definite final diagnosis were 18%, 5%, and 78%, respectively. Among women who had a termination of pregnancy, the median gestational age at final report was 24.9 weeks and 26.2 weeks at termination. Variation observed in some of the characteristics and outcomes between regional services were limited by small sample size.ConclusionThis study showed that of those referred, pES testing provided a diagnosis for one in three pregnancies with a fetal anomaly across England during the study period when other tests had been non-informative. Women who opted for a termination of pregnancy underwent the procedure at relatively late gestations. Earlier referral for pES, streamlining pathways, and faster turnaround times may help results to be available at an earlier gestation to allow families more time to make decisions around continuing or terminating their pregnancy. The variation in service outcomes between regional services needs to be investigated further to understand the reasons for these differences.
Published: 2024
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3. Delivery of a national prenatal exome sequencing service in England: a mixed methods study exploring healthcare professionals’ views and experiences

Author: Michelle Peter, Rhiannon Mellis, Hannah McInnes-Dean, Morgan Daniel, Holly Walton, Jane Fisher, Kerry Leeson-Beevers, Stephanie Allen, Emma L. Baple, Ana Beleza-Meireles, Marta Bertoli, Jennifer Campbell, Natalie Canham, Deirdre Cilliers, Jan Cobben, Jacqueline Eason, Victoria Harrison, Muriel Holder-Espinasse, Alison Male, Sahar Mansour, Alec McEwan, Soo-Mi Park, Audrey Smith, Alison Stewart, Dagmar Tapon, Pradeep Vasudevan, Denise Williams, Wing Han Wu, Lyn S. Chitty, and Melissa Hill
Subjects: prenatal exome sequencing, prenatal diagnosis, genomic sequencing, healthcare professionals, genetic services, service evaluation, Genetics, QH426-470
Abstract: IntroductionIn October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS.MethodsA survey (n = 159) and semi-structured interviews (n = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future.ResultsOverall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions.ConclusionHealthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals.
Published: 2024
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4. Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Author: Marie Bernkopf, Ummi B. Abdullah, Stephen J. Bush, Katherine A. Wood, Sahar Ghaffari, Eleni Giannoulatou, Nils Koelling, Geoffrey J. Maher, Loïc M. Thibaut, Jonathan Williams, Edward M. Blair, Fiona Blanco Kelly, Angela Bloss, Emma Burkitt-Wright, Natalie Canham, Alexander T. Deng, Abhijit Dixit, Jacqueline Eason, Frances Elmslie, Alice Gardham, Eleanor Hay, Muriel Holder, Tessa Homfray, Jane A. Hurst, Diana Johnson, Wendy D. Jones, Usha Kini, Emma Kivuva, Ajith Kumar, Melissa M. Lees, Harry G. Leitch, Jenny E. V. Morton, Andrea H. Németh, Shwetha Ramachandrappa, Katherine Saunders, Deborah J. Shears, Lucy Side, Miranda Splitt, Alison Stewart, Helen Stewart, Mohnish Suri, Penny Clouston, Robert W. Davies, Andrew O. M. Wilkie, and Anne Goriely
Subjects: Science
Abstract: PREGCARE is a new strategy for families who had a child with a pathogenic de novo mutation, that efficiently identifies couples at higher recurrence risk due to parental mosaicism, while reassuring many others that their recurrence risk is negligible.
Published: 2023
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5. A patient with a germline SDHB mutation presenting with an isolated pituitary macroprolactinoma

Author: Michelle Maher, Federico Roncaroli, Nigel Mendoza, Karim Meeran, Natalie Canham, Monika Kosicka-Slawinska, Birgitta Bernhard, David Collier, Juliana Drummond, Kassiani Skordilis, Nicola Tufton, Anastasia Gontsarova, Niamh Martin, Márta Korbonits, and Florian Wernig
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient’s SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient’s father’s paraganglioma.
Published: 2018
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6. The PREGCARE study: Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Author: Marie Bernkopf, Ummi B. Abdullah, Stephen J. Bush, Katherine Wood, Sahar Ghaffari, Eleni Giannoulatou, Nils Koelling, Geoffrey J. Maher, Loïc M. Thibault, Jonathan Williams, Edward M. Blair, Fiona Blanco Kelly, Angela Bloss, Emma Burkitt-Wright, Natalie Canham, Alexander T. Deng, Abhijit Dixit, Jacqueline Eason, Frances Elmslie, Alice Gardham, Eleanor Hay, Muriel Holder, Tessa Homfray, Jane A. Hurst, Diana Johnson, Wendy D. Jones, Usha Kini, Emma Kivuva, Ajith Kumar, Melissa M. Lees, Harry G. Leitch, Jenny E. V. Morton, Andrea H. Németh, Shwetha Ramachandrappa, Katherine Saunders, Deborah J. Shears, Lucy Side, Miranda Splitt, Alison Stewart, Helen Stewart, Mohnish Suri, Penny Clouston, Robert W. Davies, Andrew O. M. Wilkie, and Anne Goriely
Abstract: Next-generation sequencing has led to a dramatic improvement in molecular diagnoses of serious pediatric disorders caused by apparently de novo mutations (DNMs); by contrast, clinicians’ ability to counsel the parents about the risk of recurrence in a future child has lagged behind. Owing to the possibility that one of the parents could be mosaic in their germline, a recurrence risk of 1-2% is frequently quoted, but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk stratification, by combining deep-sequencing of multiple tissues in the mother-father-child trio with haplotyping to determine the parental origin of the DNM. In the first 58 couples analysed (total of 59 DNMs in 49 different genes), the risk for 35 (59%) DNMs was decreased below 0.1% but for 6 (10%) couples it was increased owing to parental mosaicism - that could be quantified in semen (recurrence risks of 5.6-12.1%) for the paternal cases. Deep-sequencing of the DNM efficiently identifies couples at greatest risk for recurrence and may qualify them for additional reproductive technologies. Haplotyping can further reassure many other couples that their recurrence risk is very low, but its implementation is more technically challenging and will require better understanding of how couples respond to information that reduces their risks.
Published: 2022
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7. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct fromKabuki syndrome

Author: Karen Stals, Sara Cuvertino, Víctor Faundes, Frances Flinter, Lihadh Al-Gazali, Santina Venuto, Vagheesh M. Narasimhan, Laura Southgate, Colin A. Johnson, Eamonn Sheridan, Nisha Nair, Anne Barton, Alice Colyer, Susan J. Kimber, Brian R. Jackson, Adam Stevens, Daniel Weisberg, Natalie Canham, Giuseppe Merla, Gabriella Maria Squeo, Richard C. Trembath, Sally Ann Lynch, Fatima Nadat, Terence Garner, Robert Sellers, Sian Ellard, Muriel Holder-Espinasse, David A. van Heel, Michelle Peckham, Francesca Montanari, Siddharth Banka, Verity L. Hartill, Marco Seri, Jozef Hertecant, Cuvertino, S., Hartill, V., Colyer, A., Garner, T., Nair, N., Al-Gazali, L., Canham, N., Faundes, V. Flinter F., Hertecant, J., Holder-Espinasse, M., Jackson, B., Lynch, Sa, Nadat, F., Narasimhan, V., Peckham, M., Sellers, R., Seri, M., Montanari, F., Southgate, L., Squeo, Gm, Trembath, R., van Heel, D., Venuto, S., Weisberg, D., Stals, K., Ellard, S., The, 100, Barton, A., Kimber, S., Sheridan, E., Merla, G, Stevens, A., Johnson, Ca, Banka, S., Cuvertino S., Hartill V., Colyer A., Garner T., Nair N., Al-Gazali L., Canham N., Faundes V., Flinter F., Hertecant J., Holder-Espinasse M., Jackson B., Lynch S.A., Nadat F., Narasimhan V.M., Peckham M., Sellers R., Seri M., Montanari F., Southgate L., Squeo G.M., Trembath R., van Heel D., Venuto S., Weisberg D., Stals K., Ellard S., Barton A., Kimber S.J., Sheridan E., Merla G., Stevens A., Johnson C.A., and Banka S.
Subjects: Genetics, 0303 health sciences, Kabuki syndrome, Hearing loss, KMT2D, Choanal atresia, Biology, intrinsically disordered region, medicine.disease, Article, Human genetics, multiple congenital anomaly, 03 medical and health sciences, Exon, 0302 clinical medicine, 030220 oncology & carcinogenesis, DNA methylation, medicine, Missense mutation, medicine.symptom, histone 3 lysine 4 methyltransferase, Haploinsufficiency, Genetics (clinical), 030304 developmental biology
Abstract: Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to alpha helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
Published: 2020
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8. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author: Ashley N. Sigafoos, Salima El Chehadeh, Marcia C. Willing, Ela Akay, Florian Cherik, Anne-Marie E. Goyette, Vinodh Narayanan, Diane Masser-Frye, Catherine Karimov, Rhonda E. Schnur, Rebekah Bressi, Rhys H. Thomas, Gary D. Clark, Tina Barbaro-Dieber, Jill A. Rosenfeld, Carlos A. Bacino, Maria J. Guillen Sacoto, Laura Russell, Kristin Lindstrom, Caroline Schluth-Bolard, Xia Wang, Yvonne Hilhorst-Hofstee, Marcelo Vargas, Zehua Zhu, Ash Zawerton, Boris Keren, Mariëtte J.V. Hoffer, Isabelle Marey, Alice Poisson, Daphné Lehalle, Maries Joseph, Gaetan Lesca, Simon Zwolinski, Laurence Perrin, Rhoda Akilapa, Emilia K. Bijlsma, Christel Depienne, Amélie Piton, Claire G. Salter, Lucie Dupuis, Daryl A. Scott, Jolien S. Klein Wassink-Ruiter, Benjamin Cogné, Mathilde Nizon, Richard Chang, Kirsty McWalter, Myriam Srour, Perrine Charles, Anne-Claude Tabet, Natalie Canham, Sylvie Odent, Caroline Nava, Karl J. Clark, Elizabeth J. Bhoj, Jonathan Levy, Keri Ramsey, Yves Alembik, Lucia Ortega, Sophie Dupuis-Girod, Shoji Ichikawa, Christine Francannet, Marta Bertoli, Christèle Dubourg, Eric W. Klee, Ange-Line Bruel, Sebastien Moutton, Emily Fassi, Anthony Vandersteen, Abdul Haseeb, Antonina Wojcik, Patrick R. Blackburn, Lynne M. Bird, Patrick Rump, Véronique Lefebvre, Alma Kuechler, Sophie Nambot, Keren Machol, Cyril Mignot, Andreas Hartmann, Rossana Sanchez Russo, Erica H. Gerkes, Sylvie Jaillard, Roberto Mendoza-Londono, Trevor Cole, Pauline Monin, Cleveland Clinic, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, This research was funded in part by the Agence Nationale de la Recherche and European High-Functioning Autism Network (ANR EUHFAUTISM), the Assistance Publique–Hôpitaux de Paris (AP-HP), the Institut National de la Santé et de la Recherche Médicale (INSERM), the BioPsy labex (to Christel Depienne and C.N.) and the Association Française du Syndrome Gilles de la Tourette (AFSGT) to Christel Depienne. It was also funded by the Cleveland Clinic Lerner Research Institute (LRI Chair’s Innovative Research Award to V.L.), and by Harper’s Quest and the LAMSHF Syndrome Research Fund (donations to V.L.) and the Center for Individualized Medicine, Mayo Clinic. This study makes use of data generated by the DECIPHER community and the Deciphering Developmental Disorders (DDD) Study, which is funded by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network., We thank the patients and their families for their participation in this study, and the C4RCD Research Group (Newell Belnap, Amanda Courtright, Ana Claasen, David Craig, Matt Huentelman, Madison LaFleur, Sampathkumar Rangasamy, Ryan Richholt, Isabelle Schrauwen, Ashley L. Siniard, and Szabolics Szelinger) for providing clinical information on patient P18., Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Medizin, Haploinsufficiency, L-SOX5, VARIANTS, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics, Pediatric, Genetics & Heredity, 0303 health sciences, Pedigree, FAMILY, DNA-Binding Proteins, developmental delay, TRANSCRIPTION FACTORS, Phenotype, intellectual disability, Child, Preschool, missense variants, Female, SOXD Transcription Factors, Adult, EXPRESSION, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Mutation, Missense, autism, Cell fate determination, Biology, LONG FORM, SEQUENCE, Article, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, CARTILAGE, Intellectual Disability, medicine, Animals, Humans, Language Development Disorders, Genetic Predisposition to Disease, Preschool, Transcription factor, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, Human Genome, Infant, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, Deciphering Developmental Disorder Study, Mutation, Autism, epilepsy, Missense, 030217 neurology & neurosurgery, GENERATION
Abstract: International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
Published: 2020
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9. The ARID1B spectrum in 143 patients

Author: Catherine Vincent-Delorme, Claudia A. L. Ruivenkamp, Marjan De Rademaeker, Francisco Martínez, Tracy Dudding-Byth, Marianne McGuire, Bert B.A. de Vries, Mitsuhiro Kato, Levinus A. Bok, Hülya Kayserili, Jeff M. Milunsky, Suzanne C E H Sallevelt, Alwin F. J. Brouwer, Jill Clayton-Smith, Emilia K. Bijlsma, Miranda Splitt, Patricia G. Wheeler, Philippe M. Campeau, Fatma Mujgan Sonmez, Kylin Lammers, Stefanie Beck-Wödl, Caroline Rooryck, Louise C. Wilson, Evan E. Eichler, Sarina G. Kant, Johanna C. Herkert, Karin R. Heitink, Eyyup Uctepe, Pleuntje J. van der Sluijs, Miho Adachi-Fukuda, Lone W. Laulund, Sandra Jansen, Nicolette S. den Hollander, Damien Lederer, Tomoki Kosho, Constance T. R. M. Stumpel, Saskia M. Maas, Esra Kılıç, Erica H. Gerkes, Duco Steenbeek, Melissa Lees, Kay Metcalfe, Karin Dahan, Ineke van der Burgt, Isabelle Maystadt, Christian Netzer, Ute Grasshoff, Carmen Orellana, Mahmut Şamil Sağıroğlu, Gijs W. E. Santen, Pelin Ozlem Simsek-Kiper, Mónica Roselló, Gabriela Soares, Alexander P.A. Stegmann, Stephen P. Robertson, Adila Al-Kindy, Maian Roifman, Saori Tanabe, Vera Riehmer, Brain H Y Chung, Arie van Haeringen, G. Eda Utine, Yasemin Alanay, Rogier Kersseboom, John B. Moeschler, Barbara Oehl-Jaschkowitz, Katherine Berry, Denise Horn, Alice Gardham, Shane McKee, Anwar Baban, Amparo Sanchis Calvo, Golder N. Wilson, Krystyna H. Chrzanowska, G. M. S. Mancini, Ellen R. Elias, Małgorzata Krajewska-Walasek, Rolph Pfundt, Sarju G. Mehta, Fabienne G. Ropers, Seiji Mizuno, David Hunt, Caroline Pottinger, Dagmar Wieczorek, Yoyo W. Y. Chu, Laurent Pasquier, Bernd Wollnik, Nobuhiko Okamoto, Sunita Venkateswaran, Vanesa López-González, Natalie Canham, Blanca Gener, Anne Destree, Christina Fagerberg, Rachel K. Earl, Sharon N M Olminkhof, Nursel Elcioglu, Charlotte W. Ockeloen, Carlo Marcelis, Samantha A. Vergano, Hermine E. Veenstra-Knol, Anneke T. Vulto-van Silfhout, Allan Bayat, Catheline Vilain, Lucia Solaeche, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), Klinische Genetica, van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Woedl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F. J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W. Y., Chung, Brain H. Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hulya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, Lopez-Gonzalez, Vanesa, Maas, Saskia, Mancini, Grazia M. S., Marcelis, Carlo, Martinez, Francisco, Maystadt, Isabelle, McGuire, Marianne, McKee, Shane, Mehta, Sarju, Metcalfe, Kay, Milunsky, Jeff, Mizuno, Seiji, Moeschler, John B., Netzer, Christian, Ockeloen, Charlotte W., Oehl-Jaschkowitz, Barbara, Okamoto, Nobuhiko, Olminkhof, Sharon N. M., Orellana, Carmen, Pasquier, Laurent, Pottinger, Caroline, Riehmer, Vera, Robertson, Stephen P., Roifman, Maian, Rooryck, Caroline, Ropers, Fabienne G., Rosello, Monica, Ruivenkamp, Claudia A. L., Sagiroglu, Mahmut S., Sallevelt, Suzanne C. E. H., Sanchis Calvo, Amparo, Simsek-Kiper, Pelin O., Soares, Gabriela, Solaeche, Lucia, Sonmez, Fatma Mujgan, Splitt, Miranda, Steenbeek, Duco, Stegmann, Alexander P. A., Stumpel, Constance T. R. M., Tanabe, Saori, Uctepe, Eyyup, Utine, G. Eda, Veenstra-Knol, Hermine E., Venkateswaran, Sunita, Vilain, Catheline, Vincent-Delorme, Catherine, Vulto-van Silfhout, Anneke T., Wheeler, Patricia, Wilson, Golder N., Wilson, Louise C., Wollnik, Bernd, Kosho, Tomoki, Wieczorek, Dagmar, Eichler, Evan, Pfundt, Rolph, de Vries, Bert B. A., Clayton-Smith, Jill, Santen, Gijs W. E., Erasmus MC other, Clinical Genetics, Human Genetics, and Acibadem University Dspace
Subjects: Male, 0301 basic medicine, Hypertrichosis, Pediatrics, cuello, bias, Coffin–Siris syndrome, Chromosomal Proteins, Non-Histone, humanos, adolescente, Penetrance, PHENOTYPE, 0302 clinical medicine, Genotype, Intellectual disability, Exome, Coffin-Siris syndrome, Child, mediana edad, Genetics (clinical), Exome sequencing, factores de transcripción, adulto, Middle Aged, estudios de asociación genética, 3. Good health, DNA-Binding Proteins, intellectual disability, Child, Preschool, discapacidad intelectual, penetrancia, Female, Hand Deformities, Congenital, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Adolescent, Micrognathism, Article, CHROMATIN-REMODELING COMPLEX, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, cara, micrognatismo, Human Phenotype Ontology, medicine, Humans, Abnormalities, Multiple, mutación, Long eyelashes, Genetic Association Studies, lactante, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, MUTATIONS, proteínas de unión al ADN, Infant, Newborn, Genetic Variation, Infant, ARID1B, Hand Deformities, Phalanx, medicine.disease, variación genética, deformidades de la mano, exoma, 030104 developmental biology, Face, Mutation, business, Neck, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)
Published: 2019
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10. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

Author: Jonathan Rodgers, Antonia Marchese, Frances Elmslie, Claudine Rieubland, Noriko Miyake, Sophie Julia, Ingrid Scurr, Emmanuel Scalais, Diana S. Johnson, Elise Brischoux-Boucher, Melissa Byler, Lisa Bradley, Julie McGaughran, Siddharth Banka, Maria Gnazzo, Robert Roger Lebel, Stephanie Goh, Damien Lederer, Jane A. Hurst, Maria Cristina Digilio, Ineke van der Burgt, Nobuhiko Okamoto, Mohnish Suri, Víctor Faundes, Rhoda Akilapa, Harinder Gill, Hans T. Bjornsson, Edmond G. Lemire, Saskia Bulk, Katherine Lachlan, Han G. Brunner, Andrew E. Fry, Eric Gershon, Maria Lisa Dentici, Erina Sasaki, Valérie Benoit, Heidre Bezuidenhout, Natalie Canham, Naomichi Matsumoto, Angela F. Brady, Declan Cody, Meriel McEntagart, Seiji Mizuno, and Francesca Romana Lepri
Subjects: Male, 0301 basic medicine, Joint hypermobility, Microcephaly, Hearing loss, 610 Medicine & health, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Abnormalities, Multiple, Genetic Association Studies, Genetics (clinical), Histone Demethylases, Genetics, Sex Characteristics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Variant type, Infant, Newborn, medicine.disease, Hematologic Diseases, Phenotype, Neoplasm Proteins, DNA-Binding Proteins, 030104 developmental biology, Vestibular Diseases, Face, Female, medicine.symptom, Kabuki syndrome
Abstract: Contains fulltext : 237823.pdf (Publisher’s version ) (Open Access) PURPOSE: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. METHODS: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. RESULTS: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. CONCLUSION: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
Published: 2021
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11. Mosaicism in ASXL3-related syndrome: Description of five patients from three families

Author: Katrina Prescott, Anna Platt, Sumit Punj, Meena Balasubramanian, Deciphering Developmental Disorders Study, Schaida Schirwani, Sahar Mansour, Natalie Hauser, and Natalie Canham
Subjects: 0301 basic medicine, Male, Developmental Disabilities, Germline mosaicism, Disease, 030105 genetics & heredity, Saliva sample, Biology, Germline, 03 medical and health sciences, Neurodevelopmental disorder, Genetics, medicine, Humans, Child, Gene, Genetics (clinical), Mechanism (biology), Mosaicism, General Medicine, medicine.disease, Pedigree, genomic DNA, 030104 developmental biology, Child, Preschool, Mutation, Female, Transcription Factors
Abstract: De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome.
Published: 2020

12. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author: Enrico D.H. Konrad, Niels Nardini, Almuth Caliebe, Inga Nagel, Dana Young, Gabriella Horvath, Stephanie L. Santoro, Christine Shuss, Alban Ziegler, Dominique Bonneau, Marlies Kempers, Rolph Pfundt, Eric Legius, Arjan Bouman, Kyra E. Stuurman, Katrin Õunap, Sander Pajusalu, Monica H. Wojcik, Georgia Vasileiou, Gwenaël Le Guyader, Hege M. Schnelle, Siren Berland, Evelien Zonneveld-Huijssoon, Simone Kersten, Aditi Gupta, Patrick R. Blackburn, Marissa S. Ellingson, Matthew J. Ferber, Radhika Dhamija, Eric W. Klee, Meriel McEntagart, Klaske D. Lichtenbelt, Amy Kenney, Samantha A. Vergano, Rami Abou Jamra, Konrad Platzer, Mary Ella Pierpont, Divya Khattar, Robert J. Hopkin, Richard J. Martin, Marjolijn C.J. Jongmans, Vivian Y. Chang, Julian A. Martinez-Agosto, Outi Kuismin, Mitja I. Kurki, Olli Pietiläinen, Aarno Palotie, Timothy J. Maarup, Diana S. Johnson, Katja Venborg Pedersen, Lone W. Laulund, Sally A. Lynch, Moira Blyth, Katrina Prescott, Natalie Canham, Rita Ibitoye, Eva H. Brilstra, Marwan Shinawi, Emily Fassi, Heinrich Sticht, Anne Gregor, Hilde Van Esch, Christiane Zweier, Graduate School, Clinical Genetics, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Center for Population, Health and Society, Centre of Excellence in Complex Disease Genetics, and Aarno Palotie / Principal Investigator
Subjects: Male, CCCTC-Binding Factor, Developmental Disabilities, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Transcriptome, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Drosophila Proteins, Missense mutation, TOOL, Genetics(clinical), Child, Genetics (clinical), Genetics & Heredity, Genetics, 0303 health sciences, biology, GENE ONTOLOGY, neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMANS, Chromatin, 3. Good health, DROSOPHILA, Drosophila melanogaster, intellectual disability, LIBRARY, Female, INACTIVATION, Life Sciences & Biomedicine, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], EXPRESSION, DATABASE, Mutation, Missense, Article, Young Adult, 03 medical and health sciences, Exome Sequencing, medicine, Animals, Gene, 030304 developmental biology, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Gene Expression Profiling, biology.organism_classification, medicine.disease, CTCF, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, 030217 neurology & neurosurgery, Transcription Factors, chromatin organization
Abstract: PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published
Published: 2019
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13. Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review

Author: Neeti Ghali, Vinod Varghese, Frances Gibbon, Andrew E. Fry, Andrew G. L. Douglas, Meena Balasubramanian, Catharina (Nienke) M.L. Volker-Touw, Sally Ann Lynch, Mayy El Gamal, Michael Parker, Anna Durkin, Katherine Lachlan, Denise Williams, Alice Gardham, Volker Straub, Ruth Newbury-Ecob, Virginia Clowes, Ana Beleza, Shadi Albaba, Jenny Morton, Natalie Canham, and Peter D Turnpenny
Subjects: 0301 basic medicine, Proband, Male, Pediatrics, medicine.medical_specialty, Microcephaly, Adolescent, Haploinsufficiency, Heterogeneous-Nuclear Ribonucleoprotein U, 030105 genetics & heredity, Craniofacial Abnormalities, 03 medical and health sciences, Pregnancy, Seizures, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Craniofacial, Child, Genetics (clinical), Exome sequencing, Genetic testing, medicine.diagnostic_test, business.industry, Brain, Infant, Syndrome, medicine.disease, 030104 developmental biology, Palpebral fissure, Neurodevelopmental Disorders, Child, Preschool, Female, business
Abstract: With advances in genetic testing and improved access to such advances, whole exome sequencing is becoming a first-line investigation in clinical work-up of children with developmental delay/intellectual disability (ID). As a result, the need to understand the importance of genetic variants and its effect on the clinical phenotype is increasing. Here, we report on the largest cohort of patients with HNRNPU variants. These 21 patients follow on from the previous study published by Yates et al. in 2017 from our group predominantly identified from the Deciphering Developmental Disorders study that reported seven patients with HNRNPU variants. All the probands reported here have a de novo loss-of-function variant. These probands have craniofacial dysmorphic features, in the majority including widely spaced teeth, microcephaly, high arched eyebrows, and palpebral fissure abnormalities. Many of the patients in the group also have moderate to severe ID and seizures that tend to start in early childhood. This series has allowed us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency, and expand substantially on already published literature on HNRNPU-related neurodevelopmental syndrome.
Published: 2019

14. Congenital hyperinsulinism due to mutations in HNF1A

Author: Natalie Canham, Mohammed Didi, Senthil Senniappan, Kevin Colclough, Anuja Natarajan, Indraneel Banerjee, Daphne Yau, and Ruchi Parikh
Subjects: Male, endocrine system, Mutation, Missense, Maturity onset diabetes of the young, INDEL Mutation, Diabetes mellitus, Genetics, Medicine, Missense mutation, Humans, Hepatocyte Nuclear Factor 1-alpha, Child, Genetics (clinical), business.industry, General Medicine, medicine.disease, Phenotype, HNF1A, Pedigree, Child, Preschool, Congenital hyperinsulinism, Congenital Hyperinsulinism, Female, Metabolic syndrome, business, Haploinsufficiency
Abstract: Congenital hyperinsulinism is a rare but significant cause of severe and persistent hypoglycaemia in infancy. Although a biphasic phenotype of congenital hyperinsulinism in infancy followed by Maturity-Onset Diabetes of the Young (MODY) in later life has been established for HNF4A, the existence of a similar phenotype for a related MODY gene, HNF1A, is less clear. We describe two cases of congenital hyperinsulinism in association with dominantly inherited variants in HNF1A. They presented in the early neonatal period with unequivocal biochemical evidence of congenital hyperinsulinism and persistence into childhood with ongoing need for medical therapy. Both cases inherited HNF1A variants from a parent with a diabetes phenotype consistent with MODY, without obesity, insulin resistance or other metabolic syndrome features. In the first case, a paternally inherited novel c.-230_-101del variant was found that deletes the minimal promoter region presumably required for HNF1A expression. In the second case, a maternally inherited missense variant (c.713G>T, p.(Arg238Met)) was identified. This variant is predicted to cause haploinsufficiency via aberrant splicing and has previously been associated with MODY but not congenital hyperinsulinism. Our cases further strengthen the evidence for HNF1A as a CHI-causing gene requiring long-term follow-up.
Published: 2019

15. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019
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16. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author: Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev
Subjects: Male, 0301 basic medicine, Retinal degeneration, Biallelic Mutation, RHOA, PROTEIN, Eye, Medical and Health Sciences, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Exome, Aetiology, Genetics (clinical), Genetics & Heredity, Genetics, biology, Retinal Degeneration, Cell Polarity, MOSAIC EYES, Biological Sciences, Middle Aged, Phenotype, inherited retinal dystrophy, Pedigree, UK Inherited Retinal Disease Consortium, Female, apicobasal polarity, Retinal Dystrophies, Adult, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, Genotype, Mutation, Missense, Nerve Tissue Proteins, Retina, 03 medical and health sciences, Rare Diseases, retinitis pigmentosa, Report, CRB1, Retinitis pigmentosa, medicine, Humans, Amino Acid Sequence, Eye Proteins, Eye Disease and Disorders of Vision, Alleles, Human Genome, Neurosciences, Genetic Variation, Membrane Proteins, Epithelial Cells, Retinal, CELL FEATURES, medicine.disease, NUCLEOTIDE EXCHANGE FACTOR, p114RhoGEF, 030104 developmental biology, INTEGRATIVE GENOMICS VIEWER, OKO-MEDUZY, chemistry, Mutation, MORPHOGENESIS, 030221 ophthalmology & optometry, biology.protein, Missense, rhoA GTP-Binding Protein, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract: Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.
Published: 2017
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17. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author: Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract: Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
Published: 2017
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18. Angelman Syndrome due to a Maternally Inherited Intragenic Deletion Encompassing Exons 7 and 8 of the UBE3A Gene

Author: Athina Ververi, Beverley Bewes, Louise Busby, Natalie Canham, Lily Islam, and Caroline Sullivan
Subjects: 0301 basic medicine, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Microcephaly, Ataxia, Genetic counseling, 030105 genetics & heredity, Biology, medicine.disease, 03 medical and health sciences, Angelman syndrome, UBE3A, medicine, Multiplex ligation-dependent probe amplification, medicine.symptom, Allele, Molecular Biology, Genetics (clinical), Aunt
Abstract: Angelman syndrome (AS) is characterised by developmental delay, lack of speech, seizures, a characteristic behavioural profile with a happy demeanour, microcephaly, and ataxia. More than two-thirds of cases are due to an approximately 5-Mb interstitial deletion of the imprinted region 15q11.2q13, which is usually de novo. The rest are associated with point mutations in the UBE3A gene, imprinting defects, and paternal uniparental disomy. Small intragenic UBE3A deletions have rarely been described. They are usually maternally inherited, increasing the recurrence risk to 50%, and may be missed by conventional testing (methylation studies and UBE3A gene sequencing). We describe a boy with AS due to an 11.7-kb intragenic deletion. The deletion was identified by array-CGH and was subsequently detected in his affected first cousin and unaffected maternal grandfather, mother, and aunt, confirming the silencing of the paternal allele. The patient had developmental delay, speech impairment, a happy demeanour, microcephaly, and an abnormal EEG, but no seizures by the age of 4 years. Delineation of the underlying genetic mechanism is of utmost importance for reasons of genetic counselling, as well as appropriate management and prognosis. Alternative techniques, such as array-CGH and MLPA, are necessary when conventional testing for AS has failed to identify the underlying genetic mechanism.
Published: 2017
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19. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018
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20. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author: Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology
Subjects: 0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract: Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published
Published: 2018
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21. Correction: The ARID1B spectrum in 143 patients

Author: Mitsuhiro Kato, Grazia M.S. Mancini, Krystyna H. Chrzanowska, Alexander P.A. Stegmann, Stephen P. Robertson, Suzanne C E H Sallevelt, Yasemin Alanay, Melissa Lees, Sarju G. Mehta, Anne Destree, Emilia K. Bijlsma, Seiji Mizuno, David Hunt, Laurent Pasquier, H. lya Kayserili, Karin R. Heitink, Ineke van der Burgt, Christian Netzer, Duco Steenbeek, Mónica Roselló, Rachel K. Earl, Sharon N. M. Olminkhof, Arie van Haeringen, Katherine Berry, Ute Grasshoff, Francisco Martínez, Alwin F. J. Brouwer, Nursel Elcioglu, Patricia G. Wheeler, Rolph Pfundt, Shane McKee, Maian Roifman, Yoyo W. Y. Chu, Brain H. Y. Chung, John B. Moeschler, Barbara Oehl-Jaschkowitz, Denise Horn, Karin Dahan, Ellen R. Elias, Natalie Canham, Pelin Ozlem Simsek-Kiper, Vanesa López-González, Samantha A. Vergano, Tracy Dudding-Byth, Esra Kılıç, Charlotte W. Ockeloen, Carlo Marcelis, Levinus A. Bok, Gijs W. E. Santen, Philippe M. Campeau, Kylin Lammers, Anneke T. Vulto-van Silfhout, Stefanie Beck-Wödl, Allan Bayat, Eyyup Uctepe, Louise C. Wilson, Sarina G. Kant, Pleuntje J. van der Sluijs, Fatma Mujgan Sonmez, Tomoki Kosho, Marianne McGuire, Evan E. Eichler, Mahmut Şamil Sağıroğlu, Vera Riehmer, Caroline Rooryck, Miho Adachi-Fukuda, Rogier Kersseboom, Saskia M. Maas, Jeff M. Milunsky, Johanna C. Herkert, Anwar Baban, Nicolette S. den Hollander, Amparo Sanchis Calvo, Lone W. Laulund, Sandra Jansen, Golder N. Wilson, Kay Metcalfe, Fabienne G. Ropers, Caroline Pottinger, Gabriela Soares, Isabelle Maystadt, Miranda Splitt, Constance T. R. M. Stumpel, Catherine Vincent-Delorme, Bert B.A. de Vries, Jill Clayton-Smith, Claudia A. L. Ruivenkamp, Marjan De Rademaeker, Bernd Wollnik, Nobuhiko Okamoto, Christina Fagerberg, Erica H. Gerkes, Damien Lederer, Carmen Orellana, Alice Gardham, Saori Tanabe, Małgorzata Krajewska-Walasek, Adila Al-Kindy, Catheline Vilain, Dagmar Wieczorek, G. Eda Utine, Sunita Venkateswaran, Blanca Gener, Lucia Solaeche, and Hermine E. Veenstra-Knol
Subjects: 0303 health sciences, Coffin–Siris syndrome, Correction, medicine.disease, Genealogy, Spelling, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, medicine, Psychology, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology
Abstract: The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019
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22. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author: Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles
Subjects: 0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract: Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Published: 2017
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23. Analysis of the diagnosis, treatment and genetics of 175 cases of phaeochromocytoma and paraganglioma in two ENETS Centres of Excellence

Author: Tricia Tan, Natalie Canham, Niamh M. Martin, Emma Hatfield, Jeannie Todd, Fausto Palazzo, Neal Banga, Amir H Sam, Ashley B. Grossman, Darryl Baker, Martyn Caplin, Bernard Khoo, Christos Toumpanakis, Waljit S. Dhillo, Karim Meeran, Sophie Dean, Jonathan Harcourt, Harvinder Chahal, Basil McDonald, Florian Wernig, Kostadin Stoenchev, and Peter Clarke
Subjects: medicine.medical_specialty, Diagnosis treatment, business.industry, Excellence, Paraganglioma, media_common.quotation_subject, General surgery, Medicine, business, medicine.disease, Surgery, media_common
Published: 2017
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24. Correction: A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome

Author: Sara Cuvertino, Verity Hartill, Alice Colyer, Terence Garner, Nisha Nair, Lihadh Al-Gazali, Natalie Canham, Victor Faundes, Frances Flinter, Jozef Hertecant, Muriel Holder-Espinasse, Brian Jackson, Sally Ann Lynch, Fatima Nadat, Vagheesh M. Narasimhan, Michelle Peckham, Robert Sellers, Marco Seri, Francesca Montanari, Laura Southgate, Gabriella Maria Squeo, Richard Trembath, David van Heel, Santina Venuto, Daniel Weisberg, Karen Stals, Sian Ellard, Anne Barton, Susan J. Kimber, Eamonn Sheridan, Giuseppe Merla, Adam Stevens, Colin A. Johnson, and Siddharth Banka
Subjects: Vestibular Diseases, Face, Mutation, Correction, Humans, Abnormalities, Multiple, Hematologic Diseases, Genetics (clinical)
Abstract: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1).Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism.The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition.KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
Published: 2020

25. The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism

Author: L Panagiotakopoulos, Helen Spoudeas, Gabriela Carreno, John W. Raine, Carles Gaston-Massuet, Mark J. McCabe, Louise C. Gregory, M Rossi, John Torpiano, Cynthia L. Andoniadou, Juan Pedro Martinez-Barbera, Mehul T. Dattani, José W. Saldanha, Daniel Kelberman, Emma A Webb, and Natalie Canham
Subjects: Male, Heterozygote, medicine.medical_specialty, animal structures, Adolescent, Endocrinology, Diabetes and Metabolism, Kruppel-Like Transcription Factors, Cell Cycle Proteins, Hypopituitarism, Zinc Finger Protein Gli2, GPI-Linked Proteins, medicine.disease_cause, Growth hormone deficiency, Cohort Studies, Mice, Endocrinology, Holoprosencephaly, Internal medicine, GLI2, medicine, Animals, Humans, Hedgehog Proteins, Sonic hedgehog, Child, Zinc finger, Mutation, biology, Genetic Variation, Nuclear Proteins, Zinc Fingers, Sequence Analysis, DNA, medicine.disease, Hedgehog signaling pathway, Enhancer Elements, Genetic, Phenotype, Gene Expression Regulation, Child, Preschool, NIH 3T3 Cells, biology.protein, Female, Gene Deletion, Signal Transduction
Abstract: Summary Introduction The Gli family of zinc finger (GLI) transcription factors mediates the sonic hedgehog signalling pathway (HH) essential for CNS, early pituitary and ventral forebrain develop- ment in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE), isolated congenital hypopituitarism (CH) and cranial/midline facial abnormalities. Mutations in Sonic hedgehog (SHH) have been associated with HPE but not CH, despite murine studies indicat- ing involvement in pituitary development. Objectives/Methods We aimed to establish the role of the HH pathway in the aetiology of hypothalamo-pituitary disorders by screening our cohort of patients with midline defects and/or CH for mutations in SHH, GLI2, Shh brain enhancer 2 (SBE2) and growth-arrest specific 1 (GAS1). Results Two variants and a deletion of GLI2 were identified in three patients. A novel variant at a highly conserved residue in the zinc finger DNA-binding domain, c.1552G > A (pE518K), was identified in a patient with growth hormone deficiency and low normal free T4. A nonsynonymous variant, c.2159G > A (p.R720H), was identified in a patient with a short neck, cleft palate and hypogonadotrophic hypogonadism. A 26� 6 Mb dele- tion, 2q12� 3-q21� 3, encompassing GLI2 and 77 other genes, was identified in a patient with short stature and impaired growth. Human embryonic expression studies and molecular characteri- sation of the GLI2 mutant p.E518K support the potential pathogenicity of GLI2 mutations. No mutations were identified in GAS1 or SBE2. A novel SHH variant, c.1295T>A (p.I432N), was identified in two siblings with variable midline defects but normal pituitary function. Conclusions Our data suggest that mutations in SHH, GAS1 and SBE2 are not associated with hypopituitarism, although GLI2 is an important candidate for CH.
Published: 2014
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26. A Fetus With De Novo 2q33.2q35 Deletion Including MAP2 With Brain Anomalies, Esophageal Atresia, and Laryngeal Stenosis

Author: Joanna Jarvis, Richard J. Ellis, Josephine Wyatt-Ashmead, Kashmir Randhawa, Grazia M.S. Mancini, Natalie Canham, Ellen van Binsbergen, J Guy Thorpe-Beeston, Nadia Abdelmalik, Mieke M. van Haelst, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Other departments, and Clinical Genetics
Subjects: Microcephaly, Pathology, medicine.medical_specialty, Candidate gene, Biology, Craniofacial Abnormalities, Fetus, Genetics, medicine, Humans, Esophageal Atresia, Genetics (clinical), In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, Psychomotor retardation, Brain, Karyotype, Laryngostenosis, medicine.disease, Phenotype, Atresia, Chromosomes, Human, Pair 2, Karyotyping, Female, Autopsy, medicine.symptom, Chromosome Deletion, Laryngeal Stenosis, Microtubule-Associated Proteins, Comparative genomic hybridization
Abstract: Deletions of the long arm of chromosome 2 are rare. Few cases of interstitial deletions of the 2q33q35 region have been reported. Individuals with deletions in this region have growth retardation, psychomotor retardation, micrognathia, microcephaly, and apparently low-set ears. We describe a female fetus with a de novo deletion of 2q33.2 to q35 with delayed gyral formation with widespread neuronal heterotopia of the white matter, small cerebellum, esophageal atresia, laryngeal stenosis, micrognathia, and intrauterine growth retardation. With the use of karyotyping and high-resolution array comparative genomic hybridization the boundaries and gene content of the deletion were identified. Our aim was to determine whether a candidate gene for the brain phenotype was present in the deletion. By this means and based on literature we pinpointed the microtubule associated gene MAP2 as a candidate for the brain anomalies. (c) 2013 Wiley Periodicals, Inc.
Published: 2014
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27. A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

Author: Ray Miller, Daniel A. King, Matthew E. Hurles, Sahar Mansour, Pradeep C. Vasudevan, Diana Johnson, Tomas W Fitzgerald, Natalie Canham, Jill Clayton-Smith, and Fiona Stewart
Subjects: Genotype, Developmental Disabilities, Population, Method, Biology, Compound heterozygosity, Polymorphism, Single Nucleotide, Databases, Genetic, Genetics, Homologous chromosome, medicine, Humans, Parent-Child Relations, Child, education, Genotyping, Exome, Genetics (clinical), Exome sequencing, education.field_of_study, Chromosome Mapping, Uniparental Disomy, medicine.disease, Uniparental disomy, Software
Abstract: Exome sequencing of parent-offspring trios is a popular strategy for identifying causative genetic variants in children with rare diseases. This method owes its strength to the leveraging of inheritance information, which facilitates de novo variant calling, inference of compound heterozygosity, and the identification of inheritance anomalies. Uniparental disomy describes the inheritance of a homologous chromosome pair from only one parent. This aberration is important to detect in genetic disease studies because it can result in imprinting disorders and recessive diseases. We have developed a software tool to detect uniparental disomy from child–mother–father genotype data that uses a binomial test to identify chromosomes with a significant burden of uniparentally inherited genotypes. This tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust for use in platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1057 trios from the Deciphering Developmental Disorders project, a trio-based rare disease study, and detected six validated events, a significant enrichment compared with the population prevalence of UPD (1 in 3500), suggesting that most of these events are pathogenic. One of these events represents a known imprinting disorder, and exome analyses have identified rare homozygous candidate variants, mainly in the isodisomic regions of UPD chromosomes, which, among other variants, provide targets for further genetic and functional evaluation.
Published: 2013
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28. A Comprehensive Next Generation Sequencing–Based Genetic Testing Strategy To Improve Diagnosis of Inherited Pheochromocytoma and Paraganglioma

Author: Shirley Hodgson, Patrick J. Morrison, Yvonne Wallis, Fiona Macdonald, Trevor Cole, Ajith Kumar, Emma R. Woodward, Mariam Jafri, Márta Korbonits, Natalie Canham, Eleanor Rattenberry, Hayley Bair, Anna Yeung, Eamonn R. Maher, Fiona Lalloo, K McKay, Louise Izatt, Lindsey Vialard, Judit Dénes, and Richard M. Irving
Subjects: medicine.medical_specialty, SDHB, Endocrinology, Diabetes and Metabolism, DNA Mutational Analysis, Clinical Biochemistry, Adrenal Gland Neoplasms, SDHA, Context (language use), Pheochromocytoma, Sensitivity and Specificity, Biochemistry, Cohort Studies, Paraganglioma, Endocrinology, Cost Savings, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Prospective Studies, Germ-Line Mutation, Genetic testing, medicine.diagnostic_test, business.industry, Proto-Oncogene Proteins c-ret, Biochemistry (medical), Health Care Costs, medicine.disease, United Kingdom, Succinate Dehydrogenase, Protein Subunits, Head and Neck Neoplasms, Von Hippel-Lindau Tumor Suppressor Protein, Costs and Cost Analysis, SDHD, business
Abstract: Pheochromocytomas and paragangliomas are notable for a high frequency of inherited cases, many of which present as apparently sporadic tumors.The objective of this study was to establish a comprehensive next generation sequencing (NGS)-based strategy for the diagnosis of patients with pheochromocytoma and paraganglioma by testing simultaneously for mutations in MAX, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL.After the methodology for the assay was designed and established, it was validated on DNA samples with known genotype and then patients were studied prospectively.The study was performed in a diagnostic genetics laboratory.DNA samples from 205 individuals affected with adrenal or extraadrenal pheochromocytoma/head and neck paraganglioma (PPGL/HNPGL) were analyzed. A proof-of-principle study was performed using 85 samples known to contain a variant in 1 or more of the genes to be tested, followed by prospective analysis of an additional 120 samples.We assessed the ability to use an NGS-based method to perform comprehensive analysis of genes implicated in inherited PPGL/HNPGL.The proof-of-principle study showed that the NGS assay and analysis gave a sensitivity of 98.7%. A pathogenic mutation was identified in 16.6% of the prospective analysis cohort of 120 patients.A comprehensive NGS-based strategy for the analysis of genes associated with predisposition to PPGL and HNPGL was established, validated, and introduced into diagnostic service. The new assay provides simultaneous analysis of 9 genes and allows more rapid and cost-effective mutation detection than the previously used conventional Sanger sequencing-based methodology.
Published: 2013
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29. Heterozygous mutations affecting the protein kinase domain of

Author: Mark J, Hamilton, Richard C, Caswell, Natalie, Canham, Trevor, Cole, Helen V, Firth, Nicola, Foulds, Ketil, Heimdal, Emma, Hobson, Gunnar, Houge, Shelagh, Joss, Dhavendra, Kumar, Anne Katrin, Lampe, Isabelle, Maystadt, Victoria, McKay, Kay, Metcalfe, Ruth, Newbury-Ecob, Soo-Mi, Park, Leema, Robert, Cecilie F, Rustad, Emma, Wakeling, Andrew O M, Wilkie, The Deciphering Developmental Disorders, Study, Stephen R F, Twigg, and Mohnish, Suri
Subjects: Male, Models, Molecular, Heterozygote, protein kinases, Adolescent, Developmental Disabilities, Mutation, Missense, Syndrome, congenital heart defects, Protein Domains, cdk13, Intellectual Disability, CDC2 Protein Kinase, Mutation, Humans, Thermodynamics, Female, New Disease Loci, Child, exome sequencing, Conserved Sequence, ohdo syndrome
Abstract: Introduction Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. Methods Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. Results Our cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. Conclusions These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.
Published: 2017

30. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author: Patrick Cossette, Zoha Kibar, Maxime Cadieux-Dion, Helen Brittain, Andrew E. Fry, Emily Fassi, Edward Blair, Simone Martinelli, Paul J. Benke, Guy D'Anjou, Alexandre D. Laporte, Berge A. Minassian, Sylvia Stockler, Tyson L Ware, David R. FitzPatrick, Weimin Bi, Amy L Schneider, Jill A. Rosenfeld, Shekeeb S. Mohammad, Jacques L. Michaud, Carlos A. Bacino, Joss Shelagh, Samuel F. Berkovic, Stéphane Auvin, Yunru Shao, Sylvia Dobrzeniecka, Kelly Mo, Cory Tam, Nicole Corsten-Janssen, Wendy K. Chung, Renee-Myriam Boucher, Alain Verloes, Fadi F. Hamdan, Bronwyn Kerr, Frédéric Tran Mau-Them, Martina Bebin, Philippe M. Campeau, Dara V.F. Albert, Guy A. Rouleau, Quinn Stein, Anne Lortie, Susan M. Hiatt, Lubov Blumkin, Boris Keren, Dan Spiegelman, Saadet Mercimek-Mahmutoglu, Ronald G. Lafrenière, Marie-Christine Nougues, Rhys H. Thomas, Erica H. Gerkes, Elsa Rossignol, Bruno Dallapiccola, Klaas J. Wierenga, Natalie Canham, Monica H. Wojcik, Caroline Meloche, Moira Blyth, Cyril Mignot, Heather C Mefford, Ledia Brunga, D. L. Jones, François Dubeau, Kyle Retterer, James J. O'Byrne, Christine Massicotte, Vincenzo Leuzzi, Caroline Nava, Ingrid E. Scheffer, Erik-Jan Kamsteeg, Cyrus Boelman, Megan T. Cho, Gabriela Purcarin, Brigid M. Regan, Jean Monlong, Simon Girard, Philippe Major, Marguerite Miguet, Katrin Õunap, Yu Chi Liu, Guillaume Bourque, Myriam Srour, Ousmane Diallo, Emilie Riou, Lionel Carmant, Seema R. Lalani, Christina Nassif, Robert Roger Lebel, Anna Lehman, Georgie Hollingsworth, Stéphanie Jacques, Sunita Venkateswaran, Marco Tartaglia, Candace T. Myers, Ange-Line Bruel, Danielle M. Andrade, Imad Jarjour, Peyman Bizargity, Sara J. Dorison, Jane A. Hurst, Richard E. Frye, Lynette G. Sadleir, Alan Donaldson, Fernando Scaglia, Philippe Lemay, Paola Diadori, Laura Davis-Keppen, Division of Genetic Medicine [Seattle], University of Washington [Seattle], Centre hospitalier universtaire de Montréal, Université de Montréal, Baylor College of Medicine ( BCM ), Baylor College of Medicine, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Clinical Genetics Department, St Michael's Hospital, Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, Regional Genetic Service, St Mary's Hospital, Manchester, SUNY Upstate Medical University, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Robert Debré, Universitätsklinikum Leipzig, Institute of Plant and Microbial Biology, Academia Sinica, Istituto di Genetica Medica, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanita', Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], 'Personal Protection Against Vectors' working group ( PPAV ), PPAV working group, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], McGill University and Genome Quebec Innovation Centre, Center of Excellence in Neuromics, University of Montreal, The Hospital for sick children [Toronto] ( SickKids ), CHU Sainte Justine [Montréal], Genome Canada Genome Quebec Jeanne and Jean-Louis Levesque Foundation Michael Bahen Chair in Epilepsy Research Ontario Brain Institute McLaughlin Foundation University of Toronto National Institute of Neurological Disorders and Stroke RO1 NS069605 University of Toronto McLaughlin Accelerator Grant in Genomic Medicine MC-2013-08, Baylor College of Medicine (BCM), Baylor University, State University of New York (SUNY), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 'Personal Protection Against Vectors' working group (PPAV), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), The Hospital for sick children [Toronto] (SickKids), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, 0301 basic medicine, Candidate gene, medicine.medical_specialty, medical genetics, glycosylation, Nonsense mutation, Genome-wide association study, Gene mutation, Biology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, severe intellectual disability, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, children, Recurrence, Seizures, Genetic linkage, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Journal Article, Genetics, medicine, Humans, Child, disorders, Genetics (clinical), Genetic association, Brain Diseases, disease, cis-prenyltransferase, Genome, Human, structural basis, medicine.disease, diphosphate synthase, 030104 developmental biology, Child, Preschool, Mutation, Medical genetics, Female, nogo-b receptor, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study, Meta-Analysis
Abstract: Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
Published: 2017
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31. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Author: Elena Prigmore, Christopher Thornborough, Judith A. Goodship, Koenraad Devriendt, Matthew E. Hurles, Siddharth Banka, Hashim Abdul-Khaliq, Carmel Moore, Denise Williams, Seham Osman Omer, Soo-Mi Park, Diana Rajan, Okan Toka, Ganesh J. Swaminathan, Jeffrey C. Barrett, Martin O. Pollard, Frances A. Bu'Lock, Allan Daly, Anne-Karin Kahlert, Tessa Homfray, Shoumo Bhattacharya, Catherine Cosgrove, Irina-Gabriela Colgiu, Tarjinder Singh, Ingo Daehnert, Karen P. McCarthy, Michael Parker, Brigitte Stiller, Jeroen Breckpot, U.M.M. Bauer, Anna Wilsdon, Kay Metcalfe, Dorin Manase, Ami Ketley, David R. FitzPatrick, Bernard Thienpont, Katherine Lachlan, Jeremy F. McRae, Kirstin Hoff, Helen V. Firth, Marc Gewillig, Sabine Klaassen, Seema Mital, Alan Fryer, Jennifer G. Sambrook, Kerry Setchfield, Willem H. Ouwehand, Hans-Heiner Kramer, Michael Wright, Saeed Al Turki, Jacoba Louw, Bernard Keavney, AK Lampe, Hugh Watkins, Natalie Canham, Jamie Bentham, Riyadh M. Abu-Sulaiman, Ashok Kumar Manickara, Thomas Pickardt, Alejandro Sifrim, David J. Roberts, J. David Brook, Ruth Newbury-Ecob, John Danesh, Caroline F. Wright, Leema Robert, Marc-Phillip Hitz, Felix Berger, Piers E.F. Daubeney, Emma Hobson, Tomas W Fitzgerald, and Helen Cox
Subjects: 0301 basic medicine, Proband, Male, Protein Conformation, Disease, Bioinformatics, Autoantigens, DISEASE, FAMILIES, 0302 clinical medicine, Genotype, Exome, Exome sequencing, Protein Kinase C, Sequence Deletion, Genetics & Heredity, Genetics, 11 Medical And Health Sciences, Syndrome, Deciphering Developmental Disorders Study, Penetrance, GENOTYPE, Medical genetics, Female, Life Sciences & Biomedicine, Mi-2 Nucleosome Remodeling and Deacetylase Complex, INTERVAL Study, Heart Defects, Congenital, medicine.medical_specialty, Biology, Article, 03 medical and health sciences, CDC2 Protein Kinase, Journal Article, medicine, UK10K Consortium, Humans, cardiovascular diseases, Sibling, RECURRENCE, Science & Technology, 06 Biological Sciences, FRAMEWORK, Clinical Genetics, Congenital Heart Defects, Genetics Research, 030104 developmental biology, DE-NOVO MUTATIONS, DISCOVERY, Mutation, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4, 5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6, 7. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings8. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
Published: 2016
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32. Delineating the 17q24.2–q24.3 microdeletion syndrome phenotype

Author: Jodi M. Lestner, Richard Ellis, and Natalie Canham
Subjects: Hypertrichosis, Potential candidate, Biology, Andersen–Tawil syndrome, Genetics, medicine, Humans, Child, Gene, Genetics (clinical), Fibromatosis, Gingival, Comparative Genomic Hybridization, Leg, Facies, Chromosome, General Medicine, Microdeletion syndrome, medicine.disease, Phenotype, Mild learning difficulties, Feeding problems, Female, Chromosome Deletion, Chromosomes, Human, Pair 17
Abstract: We present an 11-year-old girl with a 2.3 Mb de novo interstitial deletion in chromosome 17q24.2-q24.3 identified by array CGH. The phenotype in this case includes skeletal malformations (lower limb bowing, progressive scoliosis and dental abnormalities), feeding problems, mild learning difficulties, and a characteristic facial appearance. Much of the phenotype is attributable to the deletion of KCNJ2, which causes Andersen Tawil Syndrome (ATS), but the facial appearance is not typical. We hypothesise that the presence of mild channelopathy-related features seen in ATS may be explained by haplo-insufficiency, leading to a reduced number of functionally normal Kir2.1 channels. Comparison is made to previous reports describing overlapping 17q deletions, and potential candidate genes which account for the specific phenotypic similarities with this case are highlighted.
Published: 2012
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33. CCDC88A mutations cause PEHO-like syndrome in humans and mouse

Author: Michael S, Nahorski, Masato, Asai, Emma, Wakeling, Alasdair, Parker, Naoya, Asai, Natalie, Canham, Susan E, Holder, Ya-Chun, Chen, Joshua, Dyer, Angela F, Brady, Masahide, Takahashi, and C Geoffrey, Woods
Subjects: Male, Mice, Knockout, Microfilament Proteins, Vesicular Transport Proteins, Brain, Infant, Brain Edema, Neurodegenerative Diseases, PEHO syndrome, neurodevelopmental disorder, Pedigree, Mice, Optic Atrophy, girdin, Mutation, Animals, Humans, epilepsy, Female, microcephaly, Child, Spasms, Infantile, Reports
Abstract: P rogressive E ncephalopathy with oedema, H ypsarrhythmia and O ptic atrophy (PEHO) is a rare, neurodegenerative disorder of unknown aetiology. Nahorski et al . identify the first causative recessive mutation in CCDC88A , which encodes the actin-binding protein Girdin. The phenotype and brain anatomy of the Ccdc88a knockout mouse resemble those of human PEHO syndrome., Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with ‘early infantile epileptic encephalopathy’. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re-examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, microcephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment.
Published: 2015

34. Mitochondria DNA depletion syndrome in a infant with multiple congenital malformations, severe myopathy, and prolonged postoperative paralysis

Author: Mark Thomas, Rahul Phadke, Martino Ruggieri, Natalie Canham, Maria Kinali, and Vincenzo Salpietro
Subjects: Mitochondrial DNA, DNA Copy Number Variations, congenital malformation, Biology, Mitochondrial depletion, DNA, Mitochondrial, Delayed Emergence from Anesthesia, Aberrant subclavian artery, Fatal Outcome, Mitochondrial myopathy, VACTERL, Paralysis, medicine, Humans, Abnormalities, Multiple, Myopathy, Muscle, Skeletal, Infant, Newborn, Infant, Mitochondrial Myopathies, Perioperative, Syndrome, anaesthesia, medicine.disease, curare, Muscle relaxation, mitochondrial depletion syndrome, Anesthesia, Pediatrics, Perinatology and Child Health, Neurology (clinical), medicine.symptom
Abstract: Mitochondrial DNA depletion syndromes are an important cause of mitochondrial cytopathies in both children and adults. We describe a newborn with multiple congenital malformations including a right aberrant subclavian artery and a trachea-oesophageal fistula in whom mitochondrial depletion syndrome was unmasked by perioperative muscle relaxation. After vecuronium infusion, the infant developed an irreversible postoperative paralysis, leading to death 32 days after surgery. The present case highlights (a) the clinical heterogeneity of mitochondrial depletion syndrome; (b) the importance of rigorous antemortem and postmortem investigations when the cause of a severe myopathy is uncertain; (c) the possible coexistence of mitochondrial depletion syndrome and congenital malformations as a result of a likely abnormal antenatal embryofetal development and (d) the importance of a careful anaesthetic management of children with mitochondrial depletion syndrome, which could be prone to complications related to the possible depressive effects on mitochondrial electron transport chain mediated by some anaesthetic agents.
Published: 2015

35. De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability

Author: Susan E. Holder, F. Lucy Raymond, Michael Field, Detelina Grozeva, Soo-Mi Park, James A B Floyd, Keren J. Carss, Hayley Archer, Olivera Spasic-Boskovic, Anna Hackett, Helen V. Firth, Meredith Wilson, Natalie Canham, Michael Parker, and Matthew E. Hurles
Subjects: Male, Candidate gene, Adolescent, media_common.quotation_subject, Nonsense, Biology, medicine.disease_cause, Frameshift mutation, symbols.namesake, Report, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetics(clinical), Child, Genetics (clinical), Loss function, media_common, Mutation, Methyltransferases, Microdeletion syndrome, medicine.disease, Mendelian inheritance, symbols, Chromosomes, Human, Pair 3, Chromosome Deletion
Abstract: To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations-four nonsense (c.1195AT [p.Lys399(∗)], c.1333CT [p.Arg445(∗)], c.1866CG [p.Tyr622(∗)], and c.3001CT [p.Arg1001(∗)]) and three frameshift (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.
Published: 2014

36. Oromandibular limb hypogenesis syndrome with no oromandibular features, or Moebius syndrome without facial palsy? A diagnostic conundrum

Author: Natalie Canham
Subjects: Pediatrics, medicine.medical_specialty, Palsy, business.industry, Galton's problem, Facial Paralysis, Limb Deformities, Congenital, Syndrome, General Medicine, Mobius Syndrome, Pathology and Forensic Medicine, Diagnosis, Differential, Radiography, North west, Child, Preschool, Family medicine, Pediatrics, Perinatology and Child Health, Humans, Medicine, Abnormalities, Multiple, Female, Anatomy, business, Genetics (clinical)
Abstract: Clinical Dysmorphology 2009, 18:107–109North West Thames Regional Genetics Service (Kennedy Galton Centre),North West London Hospitals NHS Trust, Middlesex, UKCorrespondence to Dr Natalie L.E. Canham, BA(Hons), MB, ChB, North WestThames Regional Genetics Service (Kennedy Galton Centre), North WestLondon Hospitals NHS Trust, Watford Road, Harrow, Middlesex HA1 3UJ, UKTel: +44 20 8869 2767; fax: +44 20 8869 3106;e-mail: n.canham@imperial.ac.ukReceived 20 December 2007 Accepted 25 November 2008
Published: 2009
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37. Macrocephaly-cutis marmorata telangiectatica congenita: a report on the natural history of a mild case

Author: Natalie Canham and Susan E. Holder
Subjects: Adult, Peripheral Vascular Diseases, Pediatrics, medicine.medical_specialty, Adolescent, business.industry, Cutis marmorata telangiectatica congenita, Macrocephaly, General Medicine, medicine.disease, Pathology and Forensic Medicine, Natural history, Child, Preschool, Pediatrics, Perinatology and Child Health, medicine, Humans, Female, Anatomy, medicine.symptom, Child, business, Genetics (clinical), Telangiectatica Congenita
Abstract: Macrocephaly-cutis marmorata telangiectatica congenita was first identified as a distinct syndrome in 1997. Since then there have been more than 10 further reports of the condition, several also comprising reviews of the earlier literature. Virtually all reported patients, however, are young children, and there is very little information about the natural evolution of the condition in adolescence and later life. This report describes a patient with features of macrocephaly-cutis marmorata telangiectatica congenita, though mildly affected, and her progression into teenage life. Her mild problems, many of which have largely resolved, demonstrate a possible more optimistic view of the condition than is currently held. The difficulties in making the diagnosis in an adult patient are also discussed.
Published: 2008
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38. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Author: Jane Gitschier, Richard C. Trembath, Shawn K. Westaway, Jason Coryell, Carolyn Schanen, Paul Gissen, Shanaz Pasha, Nardo Nardocci, Alessandro Simonati, Jenny Morton, Beth Wilmot, Patricia L. Kramer, Isabelle Desguerre, Enrico Bertini, Colin A. Johnson, Allison Gregory, Giovanna Zorzi, Barbara Levinson, Neil V. Morgan, C. Geoffrey Woods, Natalie Canham, Amar Mubaidin, Hakan Cangul, Eamonn R. Maher, Susan J. Hayflick, Scott Sonek, Diana Rodriguez, Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı., and Cangül, Hakan
Subjects: Male, Infantile neuroaxonal dystrophy, Neurodegeneration with brain iron accumulation, Chromosomes, Human, Pair 22, INAD, NBIA, PLA2G6, Neuroferritinopathy, Pathogenesis, Nervous System, Gene, Gene locus, Phospholipase A2, Homeostasis, Missense mutation, Karak syndrome, Genetics, biology, Genetics & heredity, Brain, Syndrome, Parkinson disease, Heredodegenerative Disorders, Nervous System, Female, Heredodegenerative Disorders, Alzheimer disease, Alzheimer's disease, Human, Iron, Neuroaxonal Dystrophies, Neuroaxonal dystrophy, Article, Phospholipases A, WDR45, Hallervorden-spatz-syndrome, Frameshift mutation, medicine, Humans, Chromosome 22q, Gene mutation, Nerve degeneration, Gene mapping, medicine.disease, PANK2, Phospholipases A2, Degenerative disease, Mutation, biology.protein, Calcium, Involvement, PLA2G6 gene, Pantothenate Kinase-Associated Neurodegeneration, Neurodegeneration with Brain Iron Accumulation
Abstract: Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy ( INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A(2), in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis. United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)-R01HD050832 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Research Resources (NCRR)-M01RR000334 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Eye Institute (NEI)-R01EY012353 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Human Genome Research Institute (NHGRI)-N01HG065403 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA)-P30AG008017 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Research Resources (NCRR)-M01 RR000334 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Eye Institute (NEI)-R01 EY012353-07, R01 EY012353 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Human Genome Research Institute (NHGRI)-N01HG65403 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA)-P30 AG008017 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)-R01 HD050832-01A1, R01 HD050832 Fondazione Telethon-GTF04002
Published: 2006
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39. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients

Author: Usha Kini, Sheela Nampoothiri, Marjolijn C.J. Jongmans, Denise Horn, Gijs W. E. Santen, Emmelien Aten, M. S Mancini Grazia, Ruth Newbury-Ecob, Elizabeth Sweeney, Merel W. Boogaard, Helen Kingston, Amanda L. Collins, Tjitske Kleefstra, Christian A.C. Van der Lans, Albertien M. van Eerde, Alice Gardham, Shane McKee, Miranda Splitt, Debbie Shears, Michael J. Parker, Victoria Harrison, Natalie Canham, Saskia M. Maas, Marjolein Kriek, Martijn H. Breuning, Nancy Kramer, Leigh Anne Flore, Gozde Yesil, Luis A. Pérez-Jurado, John M. Graham, Katherine Berry, Louise Brueton, Krystyna H. Chrzanowska, I. Karen Temple, Odile Boute, M. J Ellen Vollebregt, Bert B.A. de Vries, Jill Clayton-Smith, Beyhan Tüysüz, Patrícia Maciel, Johan T. den Dunnen, Caroline Pottinger, Ronelle Snowdowne, Robert Smigiel, Mafalda Barbosa, Isabelle Maystadt, May Tassabehji, Alan Fryer, Martine J. van Belzen, Louise C. Wilson, Margherita Silengo, Helen Stewart, Mariam Almureikhi, Anneke T. Vulto-van Silfhout, Ineke van der Burgt, Seema Kapoor, Catherine Vincent-Delorme, Caroline Rooryck, Tawfeg Ben-Omran, Michiel J R van der Wielen, Nicolette S. den Hollander, John Dean, Stefania Bigoni, Jeff M. Milunsky, Bregje W.M. van Bon, Sarah M. Nikkel, Arie van Haeringen, Gabriela Soares, Ankur Singh, Raoul C.M. Hennekam, Sarina G. Kant, Alexander Hoischen, Margot M L Linssen, Stephen P. Robertson, Anwar Baban, Dragana Josifova, Krajewska-Walasek Malgorzata Krajewska-Walasek, Teresa De Toni, Kate Chandler, Ivonne J H M van Minderhout, Linda Vijfhuizen, Immunology, Universidade do Minho, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Human Genetics, Paediatrics, and Paediatric Genetics
Subjects: ARID1A, Chromosomal Proteins, Non-Histone, Coffin-Siris, Medicina Básica [Ciências Médicas], SMARCB1, Bioinformatics, Germline, NBS, SMARCA4, Micrognathism, Gene Order, SMARCA2, Exome, Genetics (clinical), Genetics, Mosaicism, Nuclear Proteins, Exons, SMARCB1 Protein, Phenotype, SMARCE1, genotype-phenotype, DNA-Binding Proteins, SWI/SNF, ARID1B, BAF, CSS, Nicolaides-Baraitser, mosaicism, Ciências Médicas::Medicina Básica, Hand Deformities, Congenital, SNF, Biology, Genotype-phenotype, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Intellectual Disability, medicine, Humans, SWI, Abnormalities, Multiple, Coffin–Siris syndrome, Genetic Association Studies, DNA Helicases, Facies, medicine.disease, Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory [NCMLS 6], Face, Multiprotein Complexes, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], Neck, Transcription Factors
Abstract: De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype-genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation., (undefined)
Published: 2013
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40. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Author: Jennifer E. Van Eyk, Margaret H. Yang, Yichun Chen, Han G. Brunner, Djahita Bjeda, Jefferson J. Doyle, Harry C. Dietz, Ernie M.H.F. Bongers, Geert Mortier, Bart Loeys, Alan C. Braverman, Elena M. Gallo, Natalie Canham, Loretha Myers, Gretchen L. Oswald, Elliot K. Fishman, Mark E. Lindsay, Janneke Timmermans, Abdallah F. Elias, Britt-Marie Anderlid, Justyna Fert-Bober, Howard P. Levy, Lut Van Laer, Marlies Kempers, Dorien Schepers, Nikhita Ajit Bolar, and Peter H. Byers
Subjects: Male, Marfan syndrome, medicine.medical_specialty, Fibrillin-1, Haploinsufficiency, 030204 cardiovascular system & hematology, Biology, Fibrillins, Thoracic aortic aneurysm, Loeys–Dietz syndrome, Article, Marfan Syndrome, Genomic disorders and inherited multi-system disorders [IGMD 3], Mice, Transforming Growth Factor beta2, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Internal medicine, Genetics, medicine, Animals, Humans, Autocrine signalling, Renal disorder [IGMD 9], 030304 developmental biology, Mice, Knockout, Loeys-Dietz Syndrome, 0303 health sciences, Aortic Aneurysm, Thoracic, Cardiovascular diseases [NCEBP 14], Microfilament Proteins, ACVRL1, Syndrome, TGF beta receptor 2, medicine.disease, Mice, Mutant Strains, Pedigree, Disease Models, Animal, Phenotype, Endocrinology, Mutation, Cancer research, Female, Human medicine, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], Signal Transduction
Abstract: Item does not contain fulltext Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-beta signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-beta signaling, including either subunit of the TGF-beta receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-beta2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-beta signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-beta signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-beta signaling and phenotypic worsening in association with normalization of TGF-beta2 expression and high expression of TGF-beta1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-beta-mediated vasculopathies.
Published: 2012

41. Distal monosomy 1p36: an atypical case with duodenal atresia and a small interstitial deletion

Author: Alex Allwood, John A. Crolla, Julia Rankin, Catherine Delmege, Natalie Canham, and Viv K. Maloney
Subjects: Pathology, medicine.medical_specialty, Monosomy, Comparative Genomic Hybridization, business.industry, Duodenum, Infant, Newborn, Infant, General Medicine, medicine.disease, Pathology and Forensic Medicine, Duodenal atresia, Text mining, Chromosomes, Human, Pair 1, Pregnancy, Child, Preschool, Pediatrics, Perinatology and Child Health, Medicine, Humans, Female, Anatomy, business, Genetics (clinical), Sequence Deletion
Published: 2009

42. The Mutational Spectrum Of Human Malignant Autosomal Recessive Osteopetrosis

Author: Natalie Canham, Anna Villa, Virginia Gulino, Amos Etzioni, Edwin M. Horwitz, Andrea Superti Furga, Antonio Musio, Gert Matthijs, Ian O. Ellis, Luigi D. Notarangelo, Jouni Väliaho, Edoardo Lanino, Johan L.K. Van Hove, Ilhan Tezcan, Anders Fasth, Hans D. Ochs, Annalisa Frattini, Massimiliano Mirolo, Verena Klamroth, Dragana Vujic, Cristina Sobacchi, Paul J. Orchard, Shigeaki Nonomaya, Sophie Dupuis-Girod, Oscar Porras, Marino Andolina, Paolo Vezzoni, Riyana Babul-Hirji, David Chitayat, Ivo Barić, Alain Fisher, Bert Gerritsen, Mauno Vihinen, and Çocuk Sağlığı ve Hastalıkları
Subjects: Male, Vacuolar Proton-Translocating ATPases, Biochemistry & Molecular Biology, DNA Mutational Analysis, Molecular Sequence Data, Genes, Recessive, Gene mutation, Biology, medicine.disease_cause, Polymerase Chain Reaction, Cell Line, TCIRG1, Chloride Channels, Genetics, medicine, Animals, Humans, Missense mutation, Amino Acid Sequence, Molecular Biology, Genetics (clinical), Genetics & Heredity, Mutation, Base Sequence, Sequence Homology, Amino Acid, Genetic heterogeneity, Chromosomes, Human, Pair 11, Infant, Newborn, Infant, Exons, General Medicine, Null allele, Introns, Haplotypes, Osteopetrosis, Vacuoles, biology.protein, Female, CLCN7, Infantile malignant osteopetrosis
Abstract: Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogenous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for similar to 50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition. (Less)
Published: 2001

43. Erratum: Corrigendum: PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Author: Neil V. Morgan, Amar Mubaidin, Hakan Cangul, Eamonn R. Maher, Isabelle Desguerre, Alessandro Simonati, Shawn K. Westaway, Jason Coryell, Shanaz Pasha, Enrico Bertini, Barbara Levinson, Beth Wilmot, Nardo Nardocci, Carolyn Schanen, Patricia L. Kramer, Allison Gregory, Scott Sonek, Diana Rodriguez, C. Geoffrey Woods, Natalie Canham, Paul Gissen, Jane Gitschier, Jenny Morton, Richard C. Trembath, Colin A. Johnson, Giovanna Zorzi, and Susan J. Hayflick
Subjects: Genetics, chemistry.chemical_compound, Phospholipase A2, chemistry, Nat, biology.protein, Biology, DNA
Abstract: Nat. Genet. 38, 752–754 (2006); published online 18 June 2006; corrected after print 17 July 2006 In the version of this article initially published, the authors neglected to acknowledge sample contributions. Samples were obtained from the “Cell line and DNA bank from patients affected by genetic diseases” collection at the Giannina Gaslini Institute (http://www.gaslini.org/labdppm.htm) supported by Italian Telethon grants (project #GTF04002).
Published: 2006
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44. An individual with Muir-Torre syndrome found to have a pathogenic MSH6 gene mutation.

Author: Angela Arnold, Stewart Payne, Samantha Fisher, Diane Fricker, Judith Soloway, Susan White, Marco Novelli, Kylie MacDonald, James Mackay, Richard Groves, and Natalie Canham
Subjects: GENETIC mutation, SYNDROMES, GENES, DIAGNOSIS, BIOLOGICAL variation
Abstract: AbstractÂ Â Mutations reported to cause Muir-Torre syndrome (MTS) have previously been reported in the mismatch repair genes MLH1 and MSH2 and more recently, in MYH [1]. We report siblings, one of whom has a clinical diagnosis of MTS, who have a pathogenic MSH6 gene mutation. This finding demonstrates that MSH6 gene analysis should be considered in MTS families where no MSH2 or MLH1 gene mutations have been found. [ABSTRACT FROM AUTHOR]
Published: 2007
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45. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Author: Nicola S. Cooper, S Samant, H Purnell, Claire L. S. Turner, A Vandersteen, Alex Magee, Susan Tomkins, Louise C. Wilson, L Greenhalgh, IK Temple, Irina Colgiu, A Duncan, G Cross, Susan E. Holder, C Wragg, Deirdre E. Donnelly, Nadia Akawi, Linda Sneddon, Eamonn Sheridan, Wendy D Jones, I Ellis, David Bourn, Joanna Poulton, Ingrid Simonic, R Singzon, Lisa Bradley, Matthew E. Hurles, Meena Balasubramanian, Dominic J. McMullan, Trevor Cole, Gillian Roberts, J Thomson, Moira Blyth, G Hollingsworth, Neeti Ghali, Alex Henderson, Zara Skitt, E Roberts, G Woods, David Goudie, J Awada, Caroline Langman, U Anjum, Martin O. Pollard, Usha Kini, Stephen Clayton, J Burn, Daniel M Barrett, Vka Kumar, Angela E. Douglas, Natalie Canham, Ruth Armstrong, Denise Williams, C Shaw-Smith, Lorraine Gaunt, S Ingram, Edward Blair, K Brunstrom, O. W.J. Quarrell, Ben Hutton, Nora Shannon, S Wallwark, Laura E Mason, Sarah F. Smithson, Jeremy F. McRae, Amanda L. Collins, Shane McKee, Katrina Prescott, Lara Cresswell, Sofia Douzgou, L Islam, C Deshpande, J Waters, Anna Middleton, S-M Park, Tarjinder Singh, Liu He, M Tein, T Fendick, B Kaemba, Tara Montgomery, Michael Wright, Jenny Morton, J Roberts, Emma Hobson, Caroline Mackie Ogilvie, Katrina Tatton-Brown, Lucy Jenkins, A Coates, Abhijit Dixit, Deborah J. Shears, Kath Smith, D. Baty, D Lim, D Cilliers, Richard Gibbons, Ruth Newbury-Ecob, M Squires, Nicola K. Ragge, Anneke Seller, E Kivuva, Kay Metcalfe, Fiona Stewart, K Marks, Elisabeth Rosser, R Fisher, Andrew E. Fry, Joan Paterson, Diana Wellesley, Dian Donnai, Christopher P. Bennett, Jonathan Berg, Ganesh J. Swaminathan, Lucy Raymond, Sally Ann Lynch, Pradeep C. Vasudevan, Rosemarie Davidson, Melita Irving, John Dean, Margo Whiteford, Melissa Lees, S Payne, K-R Ong, Emma Gray, M Holder, Dragana Josifova, Claire Kirk, McConnell, Helen Cox, Sarju G. Mehta, Elena Prigmore, Emma Shearing, Anand Saggar, Angela Barnicoat, Alejandro Sifrim, Nicola Foulds, Katherine Martin, Joanna Kaplanis, Sahar Mansour, Kirsty Ambridge, Clowes, A Procter, Z Miedzybrodzka, Katherine Lachlan, S Schweiger, E Maher, Allyson Ross, Simon Brent, C Sequeira, Tabib Dabir, Netravathi Krishnappa, Andrew Smith, B Bernhard, Andrew Green, Sara Widaa, Daniel A. King, Astrid Weber, Harinder Gill, Frances Flinter, Ruth McGowan, Siddharth Banka, Susan E. McNerlan, Elizabeth M. Sweeney, L Nevitt, Michael Parker, Hood Mugalaasi, AP Bevan, L Harrison, Varghese, Lucy Hildyard, Murday, G Kirby, S Clasper, Sutton, Clare Taylor, Andrew Jackson, A Selby, E Wilkinson, Miranda Splitt, Stuart Aitken, Shelagh Joss, Fiona Connell, Julie Vogt, Jill Clayton-Smith, Alan Fryer, N Pratt, Parthiban Vijayarangakannan, Shehla Mohammed, Susan Price, Wayne Lam, Peter D. Turnpenny, C Tysoe, Raheleh Rahbari, Marc Tischkowitz, N Williams, Tessa Homfray, Maria Bitner-Glindzicz, Helen Murphy, Meriel M. McEntagart, Sian Ellard, M Ahmed, R O'Shea, Andrew R. Norman, Daniel Perrett, Harrison, Philip Greene, David Moore, R Hawkins, DT Pilz, FitzPatrick, P Batstone, Esther Kinning, Caroline F. Wright, Yanick J. Crow, Kate Chandler, C Donnelly, Leema Robert, Straub, Susan M. Gribble, Philip Jones, D de Vries, K Evans, Simon J. Davies, Diana Baralle, E Miles, Jeffrey C. Barrett, A Lampe, Joshua C. Randall, Bruce Castle, K McKay, D Rice, Becky Treacy, Richard H Scott, Rosemary Kelsell, Angela F. Brady, Julian R. Sampson, J Jarvis, Laura Yates, R Sandford, Hayley Archer, M Yau, Mohnish Suri, Caroline Pottinger, Dhavendra Kumar, R. Taylor, Alison Kraus, L Bourdon, Alan Donaldson, S Everest, S Kazembe, Sian Morgan, C Longman, Ingrid Scurr, Alison Male, Ajoy Sarkar, Helen Kingston, Emma McCann, Julie M. Phipps, Andrea H. Németh, A Pridham, D Bohanna, C Gardiner, Diana Johnson, Tomas W Fitzgerald, Eleni A. Chatzimichali, A Dobbie, Diana Rajan, Frances Elmslie, Mohsan Alvi, Pendaran Roberts, Bronwyn Kerr, M D'Alessandro, Elizabeth A. Jones, Simon Holden, U Maye, Helen V. Firth, J Rankin, H. Stewart, S Naik, Adrian Tivey, Chirag N. Patel, Tanya Bayzetinova, G Lowther, G Devlin, A Torokwa, DJ Bunyan, Judith A. Goodship, Sarah Hewitt, Emma Wakeling, Christoffer Nellåker, S Wilcox, Saba Sharif, MN Collinson, C Brewer, Jacqueline Eason, C McWilliam, Jane A. Hurst, Angus John Clarke, Mervyn Humphreys, and Stephen W. Hellens
Subjects: Genetics, 0303 health sciences, education.field_of_study, Genetic heterogeneity, Population, Biology, Phenotype, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, education, Indel, Gene, Exome, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.AbbreviationsPTVProtein-Truncating VariantDNMDe Novo MutationDDDevelopmental DisorderDDDDeciphering Developmental Disorders study

46. Cutis aplasia as a feature of Kabuki syndrome.

Author: Natalie Canham
Published: 2006
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