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1. Telemedicine strategy of the European Reference Network ITHACA for the diagnosis and management of patients with rare developmental disorders

Author

Michael Smith, Elizabeth Alexander, Ruta Marcinkute, Dorica Dan, Myfanwy Rawson, Siddharth Banka, Jason Gavin, Hany Mina, Con Hennessy, Florence Riccardi, Francesca Clementina Radio, Marketa Havlovicova, Matteo Cassina, Adela Chirita Emandi, Melanie Fradin, Lianne Gompertz, Ann Nordgren, Rasa Traberg, Massimiliano Rossi, Aurelién Trimouille, Rasika Sowmyalakshmi, Bruno Dallapiccola, Alessandra Renieri, Laurence Faivre, Bronwyn Kerr, Alain Verloes, Jill Clayton-Smith, Sofia Douzgou, and on behalf of ERN ITHACA

Subjects
European reference network, Developmental disorders, Telemedicine, Rare disease, Medicine
Abstract

Abstract Background The European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders. Results ERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes. Conclusions We present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services.

Published
2020
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2. Patient complaints as predictors of patient safety incidents

Author

Helen Kroening, Bronwyn Kerr, James Bruce, and Iain Yardley

Subjects
patient experience, patient safety, communication, consumer engagement, Medicine (General), R5-920, Public aspects of medicine, RA1-1270
Abstract

Patients remain an underused resource in efforts to improve quality and safety in healthcare, despite evidence that they can provide valuable insights into the care they receive. This study aimed to establish whether high-level patient safety incidents (HLIs) were predictable from preceding complaints, enabling complaints to be used to prevent HLIs. For this study complaints received from November 2011 through June 2012 and HLI incident reports from April through September 2012 were examined. Complaints and HLIs were categorised according to location or specialty and the themes they included. Data were analysed to look for correlations between number of complaints and HLIs in a given area. A qualitative analysis was carried out to determine whether any complaints contained information that, if acted upon earlier, could have prevented later HLIs. In the data a total of 52 complaints and 16 HLIs were included. No correlation was established between location of HLIs and complaints. Complaints commonly focused on staff attitude, diagnostic problems and delayed treatment. HLIs most often arose from failure to recognise a patient’s deterioration and escalate appropriately or incorrect patient identification. Most HLIs were not preceded by similar complaints. However, in two instances complaints did signpost future HLIs. Patient complaints can highlight specific risks to patient safety and act as an early warning system. There is a need to devise reliable means of identifying the minority of complaints that do precede serious incidents.

Published
2015

4. Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype–phenotype correlation study

Author

Lucy Loong, Agostina Tardivo, Alexej Knaus, Mona Hashim, Alistair T. Pagnamenta, Kerstin Alt, Helena Böhrer-Rabel, Alfonso Caro-Llopis, Trevor Cole, Felix Distelmaier, Patrick Edery, Carlos R. Ferreira, Aleksandra Jezela-Stanek, Bronwyn Kerr, Gerhard Kluger, Peter M. Krawitz, Marius Kuhn, Johannes R. Lemke, Gaetan Lesca, Sally Ann Lynch, Francisco Martinez, Caroline Maxton, Hanna Mierzewska, Sandra Monfort, Joost Nicolai, Carmen Orellana, Deb K. Pal, Rafał Płoski, Oliver W. Quarrell, Monica Rosello, Małgorzata Rydzanicz, Ataf Sabir, Robert Śmigiel, Alexander P.A. Stegmann, Helen Stewart, Constance Stumpel, Elżbieta Szczepanik, Andreas Tzschach, Lynne Wolfe, Jenny C. Taylor, Yoshiko Murakami, Taroh Kinoshita, Allan Bayat, Usha Kini, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA KG Lab Specialisten (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica

Subjects
Genetics (clinical)
Abstract

PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

Published
2023

5. Normal Mid-Gestation Fetal Ultrasonography Cannot Reliably Exclude Severe Perinatal Hypophosphatasia

Author

Chibuike Iruloh, M Zulf Mughal, Amish Chinoy, Bronwyn Kerr, and Raja Padidela

Subjects
medicine.medical_specialty, Endocrinology, business.industry, Obstetrics, Endocrinology, Diabetes and Metabolism, Fetal ultrasonography, Pediatrics, Perinatology and Child Health, Mid gestation, Hypophosphatasia, Medicine, business, medicine.disease
Abstract

Introduction: Hypophosphatasia is a systemic bone disease characterized by inhibition of bone mineralization due to mutations in the ALPL gene that results in a deficiency of tissue nonspecific alkaline phosphatase. The perinatal form is the most severe. In the past, this form was lethal, although human recombinant enzyme replacement therapy has now been developed and licensed, which improves survival. Perinatal hypophosphatasia is usually suggested on antenatal ultrasonography with undermineralization of the long bones, skull, and thoracic cavity. In the UK, antenatal ultrasonography for fetal anomalies is conducted at mid-gestation (i.e., 18–21 weeks gestational age), and if normal, no further routine scans are performed. Usually, this would identify abnormalities in bone mineralization suggestive of perinatal hypophosphatasia. Cases: We describe 2 cases of perinatal hypophosphatasia where mid-gestation ultrasonography was normal. In the first case, where a previous pregnancy had been terminated for perinatal hypophosphatasia, third trimester ultrasonography revealed skeletal features of hypophosphatasia. In the second case, the diagnosis of perinatal hypophosphatasia was made only immediately after birth. Conclusion: We conclude that serial antenatal ultrasonography or antenatal genetic testing should be considered in all pregnancies with a positive family history of hypophosphatasia, as mid-gestation ultrasonography cannot reliably exclude perinatal hypophosphatasia. This is especially important given that effective enzyme replacement therapy is now available.

Published
2021

6. Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders

Author

George J Burghel, Bronwyn Kerr, Sanjeev S. Bhaskar, John Ealing, Helen Kingston, Claire Kyle, Iain A. Bruce, Helen M. Stuart, Graeme C.M. Black, Algy Taylor, Elizabeth A. Jones, Siddharth Banka, Abigail Rousseau, Suresh Somarathi, D A Gokhale, Emma Burkitt-Wright, Jamie M Ellingford, Laura Dutton, Kate Chandler, Sofia Douzgou, Leslie P Molina-Ramírez, Ronnie Wright, Adele Fairclough, William G. Newman, Tracy A Briggs, Harriet Jackson, Christopher J. Campbell, and Jill Clayton-Smith

Subjects
Proband, Pediatrics, medicine.medical_specialty, Genomics, Workload, medical, 03 medical and health sciences, Rare Diseases, Gene panel, Intellectual disability, Exome Sequencing, Genetics, medicine, genomics, Humans, Exome, genetics, Genetics (clinical), Exome sequencing, 030304 developmental biology, Retrospective Studies, 0303 health sciences, business.industry, 030305 genetics & heredity, medicine.disease, Gene selection, business, Rare disease, early diagnosis
Abstract

PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.

Published
2021

7. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Gilles Morin, Krista Bluske, Nathaniel H. Robin, Laurence Faivre, Manuela Priolo, Dihong Zhou, Evangeline Kurtz-Nelson, Tianyun Wang, Omar Sherbini, Daryl A. Scott, Karen Stals, Fabíola Paoli Monteiro, Kaifang Pang, Sara Cabet, Francesca Clementina Radio, Bruno Dallapiccola, Marjon van Slegtenhorst, Rachel K. Earl, Katheryn Grand, Maria Iascone, Alice S. Brooks, Angelo Selicorni, July K. Jean Cuevas, Paolo Gasparini, Maria Lisa Dentici, Marialetizia Motta, Britt-Marie Anderlid, Kristin Lindstrom, Berrin Monteleone, Andrea Ciolfi, Karin Weiss, Katharina Steindl, Kirsty McWalter, Rosalba Carrozzo, Ruben Boers, Helen Kingston, Kym M. Boycott, Bekim Sadikovic, Laura Schultz-Rogers, Evan E. Eichler, Laura A Cross, Alison M R Castle, Louisa Kalsner, Lucia Pedace, Marijke R. Wevers, John M. Graham, Jessica Sebastian, Antonio Vitobello, Gaetan Lesca, Alexander P.A. Stegmann, Suneeta Madan-Khetarpal, Tahsin Stefan Barakat, Abdallah F. Elias, Teresa Robert Finestra, Adeline Vanderver, Peter D. Turnpenny, Bregje W.M. van Bon, Aida Telegrafi, David J. Amor, Deepali N. Shinde, Pedro A. Sanchez-Lara, Lisenka E.L.M. Vissers, Adam Jackson, Rolph Pfundt, Alessandro Bruselles, Andres Hernandez-Garcia, Karin E. M. Diderich, Flavio Faletra, Dana H. Goodloe, Joanne Baez, Sarit Ravid, Romano Tenconi, Sarah L. Sawyer, Lynn Pais, Bronwyn Kerr, Joost Gribnau, Lauren Carter, Melissa T. Carter, Zhandong Liu, Jennifer L. Kemppainen, Jennifer MacKenzie, Jimmy Holder, Elke de Boer, Margaret Au, Taila Hartley, Carol J Saunders, Luciana Musante, Bert B.A. de Vries, Tania Vertemati Secches, Haley McConkey, Willow Sheehan, Francesca Pantaleoni, Caterina Zanus, Christophe Philippe, Chelsea Roadhouse, Stefania Lo Cicero, Sian Ellard, R. Tanner Hagelstrom, Megha Desai, Fernando Kok, Joset Pascal, Marco Tartaglia, Eric W. Klee, Eva Morava, Michael A. Levy, Peggy Kulch, Lyndon Gallacher, Erica L. Macke, Emilia Stellacci, Siddharth Banka, Kristin G. Monaghan, Anita Rauch, Meghan C. Towne, Kate Chandler, Clinical Genetics, Developmental Biology, Radio, F. C., Pang, K., Ciolfi, A., Levy, M. A., Hernandez-Garcia, A., Pedace, L., Pantaleoni, F., Liu, Z., de Boer, E., Jackson, A., Bruselles, A., Mcconkey, H., Stellacci, E., Lo Cicero, S., Motta, M., Carrozzo, R., Dentici, M. L., Mcwalter, K., Desai, M., Monaghan, K. G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P. A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., Mackenzie, J. J., Monteleone, B., Saunders, C. J., Jean Cuevas, J. K., Cross, L., Zhou, D., Hartley, T., Sawyer, S. L., Monteiro, F. P., Secches, T. V., Kok, F., Schultz-Rogers, L. E., Macke, E. L., Morava, E., Klee, E. W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D. J., Pais, L., Gallacher, L., Turnpenny, P. D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A. M. R., Carter, M. T., Kalsner, L., de Vries, B. B. A., van Bon, B. W., Wevers, M. R., Pfundt, R., Stegmann, A. P. A., Kerr, B., Kingston, H. M., Chandler, K. E., Sheehan, W., Elias, A. F., Shinde, D. N., Towne, M. C., Robin, N. H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R. T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E. C., Earl, R. K., Anderlid, B. -M., Morin, G., van Slegtenhorst, M., Diderich, K. E. M., Brooks, A. S., Gribnau, J., Boers, R. G., Finestra, T. R., Carter, L. B., Rauch, A., Gasparini, P., Boycott, K. M., Barakat, T. S., Graham, J. M., Faivre, L., Banka, S., Wang, T., Eichler, E. E., Priolo, M., Dallapiccola, B., Vissers, L. E. L. M., Sadikovic, B., Scott, D. A., Holder, J. L., Tartaglia, M., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, SHARP, Male, obesity, genotype-phenotype correlations, Autism Spectrum Disorder, PROTEIN, Chromosome Disorders, Haploinsufficiency, RNA-Binding Protein, PHENOTYPE CORRELATIONS, 1p36, distal 1p36 deletion syndrome, DNA methylome analysis, episignature, neurodevelopmental disorder, proximal 1p36 deletion syndrome, SPEN, X chromosome, Adolescent, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult, 0302 clinical medicine, Neurodevelopmental disorder, Neurodevelopmental Disorder, Intellectual disability, MOLECULAR CHARACTERIZATION, Genetics (clinical), Genetics, DNA methylome analysi, SPLIT-ENDS, Hypotonia, Autism spectrum disorder, MONOSOMY 1P36, Pair 1, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Human, DNA-Binding Protein, Biology, genotype-phenotype correlation, Chromosomes, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Report, REVEALS, medicine, Epigenetics, Preschool, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 1p36 deletion syndrome, IDENTIFICATION, MUTATIONS, medicine.disease, GENE, 030104 developmental biology, Chromosome Disorder, 030217 neurology & neurosurgery, Epigenesis
Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

8. Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations

Author

Jill E. Urquhart, Jenny Higgs, William G. Newman, Elizabeth A Martindale, Glenda M. Beaman, Bronwyn Kerr, Gauri Batra, Rajesh Madhu, Adrian S. Woolf, Naz Khan, Jill Clayton-Smith, Tracy A Briggs, Kate Chandler, and James O'Sullivan

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Microcephaly, LIG4 syndrome, LIG4, Article, Frameshift mutation, Craniofacial Abnormalities, Consanguinity, DNA Ligase ATP, Fetus, Pregnancy, Fanconi anemia, Genetics, medicine, Humans, Multicystic Dysplastic Kidney, Radial ray defects, Frameshift Mutation, Growth Disorders, Genetics (clinical), Exome sequencing, business.industry, fungi, Immunologic Deficiency Syndromes, Infant, Newborn, General Medicine, medicine.disease, Radius, Fanconi Anemia, Phenotype, Acrorenal syndrome, Cystic dysplastic kidneys, Female, Fanconi anaemia, business, Primordial dwarfism
Abstract

Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum. We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder.

Published
2020

9. DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes

Author

Michael Brudno, Andrei L. Turinsky, Sharri Cyrus, David Chitayat, Brian H.Y. Chung, Maria Iascone, Luk Ho Ming, Tom Cushing, Eri Imagawa, Ana S A Cohen, Lynne M. Bird, Nobuhiko Okamoto, Vivienne McConnell, Stephen W. Scherer, Rosanna Weksberg, Jack Brzezinski, Kopal Garg, Carol L. Clericuzio, Roberto Mendoza-Londono, Susan M. White, Tianren Wang, Miranda Splitt, Naomichi Matsumoto, Sanaa Choufani, Guiseppe Testa, Romano Tenconi, Alessandro Vitriolo, Jerry Machado, Katrina Tatton-Brown, I. Karen Temple, Cheryl Cytrynbaum, Frances Flinter, William T. Gibson, Oana Caluseriu, Bronwyn Kerr, Eric Chater-Diehl, Sarah J. Goodman, and Sally Ann Lynch

Subjects
0301 basic medicine, DNA methylation signature, Male, medicine.disease_cause, Medical and Health Sciences, Cohort Studies, Craniofacial Abnormalities, Congenital, 0302 clinical medicine, SUZ12, Child, Genetics (clinical), EED, Genetics & Heredity, Mutation, biology, Mosaicism, EZH2, Polycomb Repressive Complex 2, Biological Sciences, overgrowth syndromes, Phenotype, Neoplasm Proteins, 030220 oncology & carcinogenesis, Histone methyltransferase, Child, Preschool, DNA methylation, Female, Abnormalities, PRC2, Multiple, Hand Deformities, Congenital, Adult, Adolescent, Mutation, Missense, Computational biology, macromolecular substances, Article, 03 medical and health sciences, Young Adult, Intellectual Disability, Genetics, medicine, Congenital Hypothyroidism, Humans, Abnormalities, Multiple, Enhancer of Zeste Homolog 2 Protein, Preschool, Gene, dNaM, Infant, Reproducibility of Results, Hand Deformities, DNA Methylation, 030104 developmental biology, biology.protein, Missense, Transcription Factors
Abstract

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Published
2020

10. Telemedicine strategy of the European Reference Network ITHACA for the diagnosis and management of patients with rare developmental disorders

Author

Francesca Clementina Radio, Bruno Dallapiccola, Mélanie Fradin, Alessandra Renieri, Alain Verloes, Jill Clayton-Smith, Michael Smith, Bronwyn Kerr, Rasika Sowmyalakshmi, Dorica Dan, Matteo Cassina, Massimiliano Rossi, Marketa Havlovicova, Laurence Faivre, Con Hennessy, Sofia Douzgou, Hany Mina, Siddharth Banka, Rasa Traberg, Aurélien Trimouille, Myfanwy Rawson, Ruta Marcinkute, Elizabeth Alexander, Ann Nordgren, Adela Chirita Emandi, Florence Riccardi, Jason Gavin, and Lianne Gompertz

Subjects
medicine.medical_specialty, Telemedicine, Service (systems architecture), Developmental disorders, European reference network, Rare disease, Process (engineering), Developmental Disabilities, lcsh:Medicine, Telehealth, behavioral disciplines and activities, Rare Diseases, Intellectual disability, medicine, Humans, Data Protection Act 1998, Pharmacology (medical), Child, Genetics (clinical), Research, lcsh:R, General Medicine, medicine.disease, Patient management, Europe, Medical genetics, Medical emergency, Psychology, Delivery of Health Care
Abstract

Background The European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders. Results ERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes. Conclusions We present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services.

Published
2020

11. Proceedings of the fifth international RASopathies symposium: When development and cancer intersect

Author

Beverly Oberlander, Katherine A. Rauen, Christopher C. Gibson, Beth Stronach, John G. Albeck, Frank McCormick, William Timmer, Erin Hefner, William Y. C. Huang, Michelle Ellis, Edward C. Stites, Lisa Schoyer, Stanislav Y. Shvartsman, Ethan O. Perlstein, Suma P. Shankar, Martin McMahon, Philip J.S. Stork, Erika Yeh, Karen W. Gripp, Marc Therrien, Bruce D. Gelb, Annette Schenck, David A. Stevenson, Leslie Rogers, Lisa Schill, Cheng Sun, Bronwyn Kerr, Hélène Cavé, Brigitte C. Widemann, Corinne M. Linardic, Maxim Itkin, Steven M Fruchtman, Martin Zenker, Erik M. Ullian, Brage S. Andresen, Nancy Ratner, and Giuseppe Zampino

Subjects
0301 basic medicine, Legius syndrome, MAPK/ERK pathway, business.industry, Cancer, medicine.disease, Bioinformatics, medicine.disease_cause, Phenotype, Germline, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Costello syndrome, 030220 oncology & carcinogenesis, Genetics, medicine, Noonan syndrome, Carcinogenesis, business, Genetics (clinical)
Abstract

This report summarizes and highlights the fifth International RASopathies Symposium: When Development and Cancer Intersect, held in Orlando, Florida in July 2017. The RASopathies comprise a recognizable pattern of malformation syndromes that are caused by germ line mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Because of their common underlying pathogenetic etiology, there is significant overlap in their phenotypic features, which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, gastrointestinal and ocular abnormalities, neurological and neurocognitive issues, and a predisposition to cancer. The RAS pathway is a well-known oncogenic pathway that is commonly found to be activated in somatic malignancies. As in somatic cancers, the RASopathies can be caused by various pathogenetic mechanisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. As such, the RASopathies represent an excellent model of study to explore the intersection of the effects of dysregulation and its consequence in both development and oncogenesis.

Published
2018

12. Catalogue of inherited disorders found among the Irish Traveller population

Author

Nuala Murphy, Alan D. Irvine, Niall Byrne, F. Browne, Catriona Keenan, Siobhan O’Sullivan, Mary D. King, Melanie Cotter, Andrew Green, Simon Jones, Sean Ennis, Jillian P. Casey, Bronwyn Kerr, Joanne Hughes, Jackie Turner, Ahmad Monavari, Ina Knerr, Deborah M. Lambert, Declan Cody, Vivienne McConnell, Sally Ann Lynch, Ellen Crushell, and Kathleen M. Gorman

Subjects
0301 basic medicine, genetic structures, Population, Ethnic group, Consanguinity, Disease, White People, 03 medical and health sciences, Irish, Ethnicity, Genetics, Humans, education, Minority Groups, Genetics (clinical), education.field_of_study, Genetic Diseases, Inborn, language.human_language, Genealogy, Europe, Irish traveller, Genetics, Population, 030104 developmental biology, Geography, Endogamy, Mutation, language, Ireland, Founder effect
Abstract

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios.Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population.Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers.Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication.Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.

Published
2018

13. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Author

Sonal Mahida, Elliott H. Sherr, Elodie Lacaze, William B. Dobyns, Kosuke Izumi, Hilde Peeters, Marielle Alders, Catherine Nowak, Dawn L. Earl, Richard M. Gronostajski, Ryan J. Dean, Megan T. Cho, Anouck Schneider, Siren Berland, Patricia Blanchet, Laurence Faivre, Martin Zenker, Ina Schanze, Caitlin J. Bridges, Daniela T. Pilz, Sangamitra Boppudi, Ilse Wieland, Jens Bunt, Avni Santani, Jessica Douglas, Elaine H. Zackai, Muriel Holder-Espinasse, Linda J. Richards, Jean Baptiste Rivière, Tania Attié-Bitach, Timothy J. Edwards, Vincent Gatinois, Jacques Puechberty, Jonathan W. C. Lim, Ghayda Mirzaa, Sian Morgan, Phillis Lakeman, Steven Boogert, Samuel Huth, Marion Gérard, Denny Schanze, Florence Petit, Xiaonan Zhao, Eyal Reinstein, David Geneviève, Bronwyn Kerr, Dian Donnai, Constance Smith-Hicks, Brieana Fregeau, Amsterdam Reproduction & Development (AR&D), ACS - Pulmonary hypertension & thrombosis, Human Genetics, Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Queensland Brain Institute, University of Queensland [Brisbane], University of Amsterdam [Amsterdam] (UvA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Haukeland University Hospital, University of Bergen (UiB), GeneDx [Gaithersburg, MD, USA], University of Washington [Seattle], Seattle Children’s Hospital, University of Manchester [Manchester], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), 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)-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, FHU TRANSLAD (CHU de Dijon), University of California [San Francisco] (UC San Francisco), University of California (UC), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Lille, Children’s Hospital of Philadelphia (CHOP ), Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Kennedy Krieger Institute [Baltimore], University Hospital of Wales (UHW), University Hospitals Leuven [Leuven], University of Glasgow, Sackler Faculty of Medicine, Tel Aviv University (TAU), Perelman School of Medicine, University of Pennsylvania, This work was supported by grants from the National Healthand Medical Research Council Australia (GNT1100443 to L.J.R.), the French Ministry of Health (PHRC national 2008/2008-A00515-50), Regional Council of Burgundy/Dijon University hospital (PARI 2012), The Genesis Foundation for Children, the US National Institutes of Health under NINDS grants(1R01NS092772 and 234567890 to W.B.D., 1R01NS058721 toW.B.D. and E.H.S., and K08NS092898 to G.M.M.), and Jordan’s Guardian Angels (G.M.M.). J.W.C.L. was supported by an International Postgraduate Research Scholarship and UQ Centennial Scholarship. R.M.G. was supported by NYSTEM grants (C026714,C026429, and C030133). R.J.D. was supported by Brain Injured Children’s Aftercare Recovery Endeavours (BICARE) Fellowship.L.J.R. was supported by an NHMRC Principal Research Fellowship(GNT1005751). M.Z. was supported by a grant from the GermanMinistry of Education and Research (BMBF) (GeNeRARe01GM1519A). We acknowledge the Linkage Infrastructure, Equipment and Facilities (LIEF) grant (LE100100074) awarded to the Queensland Brain Institute for the Slide Scanner and the facilities of the National Imaging Facility (NIF) at the Centre for Advanced Imaging, University of Queensland, used in the animal experiments., European Project: 270259,EC:FP7:ICT,FP7-ICT-2009-6,TBICARE(2011), Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut de recherche en santé, environnement et travail (Irset), 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 ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), Seattle Children's Research Institute, Department of Neurology (University of California : San Francisco), University of California [San Francisco] (UCSF), University of California-University of California, Department of Medical Genetics, HMNC Brain Health, Seattle Children’s Hospital [Seattle, WA, USA], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Université de Lorraine (UL), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Pediatrics (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Regional Genetic Service, St Mary's Hospital, Manchester, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales, Center for Human Genetics, University Hospitals Leuven, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Institute, Meir Medical Center, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, School of Computer Science and Technology, Northwestern Polytechnical University [Xi'an] (NPU), Department of Biochemistry and Developmental Genomics Group, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY)-State University of New York (SUNY)-Center of Excellence in Bioinformatics and Life Sciences, Institute of Human Genetics, University Hospital Magdeburg, université de Bourgogne, LNC, Evidence based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries - TBICARE - - EC:FP7:ICT2011-02-01 - 2014-07-31 - 270259 - VALID, Otto-von-Guericke University [Magdeburg] (OVGU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of California, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital of Wales [Cardiff, UK], and Tel Aviv University [Tel Aviv]

Subjects
Male, 0301 basic medicine, chromosome 9p23, Medical and Health Sciences, Corpus Callosum, Cohort Studies, Mice, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Agenesis of the corpus callosum, Genetics (clinical), Pediatric, Genetics & Heredity, Cerebral Cortex, Mice, Knockout, Genetics, Single Nucleotide, nuclear factor I, Biological Sciences, NFIB, NFIX, developmental delay, Mental Health, Codon, Nonsense, NFIA, intellectual disability, Child, Preschool, chromosome 9p22.3, Neurological, Speech delay, Female, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Knockout, Intellectual and Developmental Disabilities (IDD), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, macrocephaly, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Rare Diseases, Behavioral and Social Science, medicine, megalencephaly, Animals, Humans, Polymorphism, Codon, Preschool, Neurosciences, Macrocephaly, medicine.disease, Brain Disorders, haploinsufficiency, NFI Transcription Factors, 030104 developmental biology, Nonsense, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, agenesis of the corpus callosum
Abstract

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:5 pages:752-768 ispartof: location:United States status: published

Published
2018

14. Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway

Author

Ami Brooks, Emma Burkitt-Wright, Susan M Huson, Richard Emsley, Jonathan Green, Shruti Garg, Amy Burns, and Bronwyn Kerr

Subjects
Heart Defects, Congenital, Male, 0301 basic medicine, Ectodermal dysplasia, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Comorbidity, Severity of Illness Index, behavioral disciplines and activities, Executive Function, 03 medical and health sciences, 0302 clinical medicine, Developmental Neuroscience, Costello syndrome, Ectodermal Dysplasia, mental disorders, Severity of illness, medicine, Humans, Child, Retrospective Studies, Intelligence Tests, Mitogen-Activated Protein Kinase Kinases, Psychiatric Status Rating Scales, Noonan Syndrome, Facies, Temporomandibular Joint Dysfunction Syndrome, medicine.disease, Failure to Thrive, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, Autism spectrum disorder, Pediatrics, Perinatology and Child Health, Failure to thrive, ras Proteins, Autism, Noonan syndrome, Female, Neurology (clinical), medicine.symptom, Psychology, 030217 neurology & neurosurgery
Abstract

Aim To investigate the cognitive and behavioural phenotype in rare disorders of the Ras/MAPK pathway, namely Noonan, cardiofaciocutaneous (CFC), and Costello syndromes, particularly prevalence of autism spectrum disorder (ASD) and attention-deficit–hyperactivity disorder (ADHD). Method Fifty children were recruited over 10 months through the regional genetics service and advertisements. A range of parent, child, and observational measures were administered including Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale. Results Using the Collaborative Programme for Excellence in Autism criteria, 12 out of 40 children with Noonan syndrome (30%) showed ASD, and 12 out of 40 (30%) with partial ASD features and 16 out of 40 (40%) showed non-ASD. The Noonan syndrome ASD group showed male dominance in a ratio of 5:1. In the CFC group, eight out of nine children met the criteria for ASD, with equal sex distribution. Additionally 19 out of 40 (48%) of the Noonan syndrome group and eight out of nine (88.9%) of the CFC group scored met clinical criteria for ADHD. Only one child was in the Costello syndrome group. Interpretation This is the first systematic study to suggest a high prevalence of ASD in Noonan and CFC syndromes, and thus offers crucial evidence to support the importance of the Ras/MAPK pathway in the aetiology of ASD. Limitations include the inevitable possibility of a sampling bias in a rare disorder study of this kind.

Published
2017

15. De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Author

A. van Haeringen, Laurence Faivre, S Tomkins, Amélie Piton, Shelagh Joss, Emmelien Aten, C I de Bie, Ruth Newbury-Ecob, Emma Kivuva, R Ibitoye, Els A. J. Peeters, Miranda Splitt, Bronwyn Kerr, F Tranmauthem, Nicola Foulds, Andrew Collins, J Kennedy, David Geneviève, Marije Koopmans, Richard Martin, Sarah F. Smithson, Nolwenn Jean-Marçais, Jacques C. Giltay, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Leiden University Medical Center (LUMC), University of Southampton, University Medical Center [Utrecht], 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), University of Glasgow, University Hospitals Bristol, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], University of Exeter Medical School, University of Exeter, Unité de Biotechnologie, Biocatalyse et Biorégulation (U3B), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), St. Michael's Hospital, Haga Teaching Hospital [Hague], University of Bristol [Bristol], Laboratoire de Diagnostic Génétique [CHU Strasbourg], and Université de Strasbourg (UNISTRA)-CHU Strasbourg

Subjects
Male, Proband, Developmental Disabilities, Developmental disorder, Mutation, Missense, Novo variants in CNOT3, Hypotonia, Haploinsufficiency, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Exome Sequencing, Genetics, medicine, Humans, Learning, Missense mutation, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Genetic Association Studies, Genetics (clinical), Exome sequencing, Behavior, 0303 health sciences, 030305 genetics & heredity, Genetic Variation, medicine.disease, United Kingdom, Musculoskeletal Abnormalities, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Muscle Hypotonia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Ireland, Sequence Alignment, Transcription Factors
Abstract

International audience; As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

Published
2019

16. 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 George’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

17. Costello syndrome: Clinical phenotype, genotype, and management guidelines

Author

William B. Dobyns, Bronwyn Kerr, Susan M. White, Karen W. Gripp, Barbara J. Sibbles, Mihir M. Thacker, Dawn H. Siegel, Suma P. Shankar, Angela E. Lin, K. Nicole Weaver, David D. Schwartz, Katherine A. Rauen, Marni E. Axelrad, David A. Stevenson, Aaron Chidekel, Kathryn C. Chatfield, Lindsey A. Morse, Daniel Doyle, and Pediatrics

Subjects
Heart Defects, Congenital, medicine.medical_specialty, Genotype, Developmental Disabilities, Clinical Sciences, Specialty, Guidelines as Topic, RASopathy, Cardiofaciocutaneous syndrome, Article, 7.3 Management and decision making, Proto-Oncogene Proteins p21(ras), Congenital, Costello syndrome, Clinical Research, Health care, Genetics, medicine, Humans, Abnormalities, Multiple, HRAS, Disease management (health), Intensive care medicine, Germ-Line Mutation, Genetics (clinical), Heart Defects, RAS/MAPK, Pediatric, HRAS mutation, business.industry, Costello Syndrome, Disease Management, Heart, Health Services, medicine.disease, MAPK, Good Health and Well Being, Phenotype, Gene Expression Regulation, management guidelines, Face, Congenital Structural Anomalies, Noonan syndrome, Management of diseases and conditions, Abnormalities, business, Multiple, RAS
Abstract

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

Published
2019

18. First international conference on RASopathies and neurofibromatoses in Asia : identification and advances of new therapeutics

Author

Vijaya Ramesh, D. Gareth Evans, Susan M Huson, Jaishri O. Blakeley, Joshi George, Ludwine Messiaen, Ype Elgersma, Rick van Minkelen, Pierre Wolkenstein, Eric Legius, Meena Upadhyaya, Shay Ben-Shachar, Anup Raji, Bruce R. Korf, Ratna Dua Puri, Katherine A. Rauen, Luis F. Parada, Miikka Vikkula, Brigitte C. Widemann, Shubha R. Phadke, Sheetal Sharda, Sheela Nampoothiri, Michael Fisher, Isabel Cordeiro, Abeer Al-Saegh, Ashok Pillai, Ian M. Frayling, Suma P. Shankar, Nancy Ratner, Scott R. Plotkin, Yemima Berman, Anant Tambe, Uday Khire, Bronwyn Kerr, Joanne Ngeow, Lee Kong Chian School of Medicine (LKCMedicine), First International Conference on RASopathies and Neurofibromatoses in Asia, and Neurosciences

Subjects
0301 basic medicine, medicine.medical_specialty, Biomedical, Neurofibromatoses, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, 030105 genetics & heredity, RASopathy, Article, Neurofibromatosis, 03 medical and health sciences, Congenital, Rare Diseases, Costello syndrome, Translational Research, medicine, Genetics, Humans, Genetic Predisposition to Disease, Medicine [Science], Molecular Targeted Therapy, Schwannomatosis, Genetics (clinical), Genetic Association Studies, Legius syndrome, Pediatric, therapy, business.industry, Neurosciences, Disease Management, signal transduction pathway, medicine.disease, Dermatology, Clinical Trial, Brain Disorders, 030104 developmental biology, Molecular Diagnostic Techniques, ras Proteins, Noonan syndrome, Mitogen-Activated Protein Kinases, business, Noonan Syndrome with Multiple Lentigines, Biomarkers, Signal Transduction
Abstract

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies. Children's Tumor Foundation; Fonds De La Recherche Scientifique ‐ FNRS, Grant/Award Numbers: T002614, T024719F; Manchester NIHR Biomedical Research Centre, Grant/Award Number: IS‐BRC‐1215‐20007; NIH/NIAMS, Grant/Award Number: R01AR062165; Axis Health Biomedicals and the Doctor's Academy; Schiller India; MedGenome; Wales Gene Park; University of Wales Trinity Saint David; Cardiff University; AstraZeneca

Published
2019

19. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

Author

Kim M. Keppler-Noreuil, Abby Sandler, Chiara Leoni, Karlyne M. Reilly, Bronwyn Kerr, Frank McCormick, Anne Goriely, David Neal Franz, Amy E. Roberts, Scott R. Plotkin, Karen W. Gripp, Michael Fisher, Bruce R. Korf, Brigitte C. Widemann, Pinar Bayrak-Toydemir, Kathryn C. Chatfield, Annette Bakker, Karin S. Walsh, Brage S. Andresen, Emma Burkitt-Wright, Florent Elefteriou, Antonio Y. Hardan, Katherine A. Rauen, Bruce D Gelb, Dawn H. Siegel, Ype Elgersma, Lisa Schill, Lisa Schoyer, David A. Stevenson, and Neurosciences

Subjects
MAPK/ERK pathway, Clinical Sciences, Ras/MAPK, ras Proteins/genetics, experimental models, RASopathy, Article, Capital Financing, Congenital, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Costello syndrome, Genetics, medicine, cancer, Humans, Family, Neurofibromatosis, rare disorders, Intersectoral Collaboration, Genetics (clinical), Pediatric, Legius syndrome, clinical trials, Clinical Trials as Topic, business.industry, Ras mapk, Neurosciences, Mitogen-Activated Protein Kinases/genetics, medicine.disease, MAPK, Inborn, Genetic Diseases, 030220 oncology & carcinogenesis, ras Proteins, Genetic Diseases, Inborn/diagnosis, Cancer research, Congenital Structural Anomalies, Noonan syndrome, Mitogen-Activated Protein Kinases, business, 030217 neurology & neurosurgery, Noonan Syndrome with Multiple Lentigines, Ras, Signal Transduction
Abstract

The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. (c) 2016 Wiley Periodicals, Inc.

Published
2016

20. 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

21. Pathogenicity and selective constraint on variation near splice sites

Author

Sebastian S. Gerety, Frances Flinter, Patrick J. Short, Esther Kinning, Matthew E. Hurles, I. Karen Temple, Diana S. Johnson, Meriel McEntagart, Jeffrey C. Barrett, Bronwyn Kerr, Tabib Dabir, Shelagh Joss, Sofia Douzgou, Giuseppe Gallone, Jill Clayton-Smith, Caroline F. Wright, David R. FitzPatrick, Jeremy F. McRae, Emma McCann, Sally Ann Lynch, Liu He, Wayne Lam, Holly Ironfield, Vivienne McConnell, Virginia Clowes, Elizabeth H. Wynn, Helen V. Firth, and Jenny Lord

Subjects
Proband, Developmental Disabilities, Biology, medicine.disease_cause, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Exome Sequencing, Genetics, medicine, Humans, Exome, splice, Gene, Genetics (clinical), Selection (genetic algorithm), Exome sequencing, 030304 developmental biology, Mutation, 0303 health sciences, Research, RNA splicing, RNA Splice Sites, 030217 neurology & neurosurgery
Abstract

Mutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.

Published
2018
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22. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Katherine L. Helbig, Robert J. Lauerer, Jacqueline C. Bahr, Ivana A. Souza, Candace T. Myers, Betül Uysal, Niklas Schwarz, Maria A. Gandini, Sun Huang, Boris Keren, Cyril Mignot, Alexandra Afenjar, Thierry Billette de Villemeur, Delphine Héron, Caroline Nava, Stéphanie Valence, Julien Buratti, Christina R. Fagerberg, Kristina P. Soerensen, Maria Kibaek, Erik-Jan Kamsteeg, David A. Koolen, Boudewijn Gunning, H. Jurgen Schelhaas, Michael C. Kruer, Jordana Fox, Somayeh Bakhtiari, Randa Jarrar, Sergio Padilla-Lopez, Kristin Lindstrom, Sheng Chih Jin, Xue Zeng, Kaya Bilguvar, Antigone Papavasileiou, Qinghe Xing, Changlian Zhu, Katja Boysen, Filippo Vairo, Brendan C. Lanpher, Eric W. Klee, Jan-Mendelt Tillema, Eric T. Payne, Margot A. Cousin, Teresa M. Kruisselbrink, Myra J. Wick, Joshua Baker, Eric Haan, Nicholas Smith, Azita Sadeghpour, Erica E. Davis, Nicholas Katsanis, Mark A. Corbett, Alastair H. MacLennan, Jozef Gecz, Saskia Biskup, Eva Goldmann, Lance H. Rodan, Elizabeth Kichula, Eric Segal, Kelly E. Jackson, Alexander Asamoah, David Dimmock, Julie McCarrier, Lorenzo D. Botto, Francis Filloux, Tatiana Tvrdik, Gregory D. Cascino, Sherry Klingerman, Catherine Neumann, Raymond Wang, Jessie C. Jacobsen, Melinda A. Nolan, Russell G. Snell, Klaus Lehnert, Lynette G. Sadleir, Britt-Marie Anderlid, Malin Kvarnung, Renzo Guerrini, Michael J. Friez, Michael J. Lyons, Jennifer Leonhard, Gabriel Kringlen, Kari Casas, Christelle M. El Achkar, Lacey A. Smith, Alexander Rotenberg, Annapurna Poduri, Alba Sanchis-Juan, Keren J. Carss, Julia Rankin, Adam Zeman, F. Lucy Raymond, Moira Blyth, Bronwyn Kerr, Karla Ruiz, Jill Urquhart, Imelda Hughes, Siddharth Banka, Ulrike B.S. Hedrich, Ingrid E. Scheffer, Ingo Helbig, Gerald W. Zamponi, Holger Lerche, Heather C. Mefford, Alexander Allori, Misha Angrist, Patricia Ashley, Margarita Bidegain, Brita Boyd, Eileen Chambers, Heidi Cope, C. Michael Cotten, Theresa Curington, Sarah Ellestad, Kimberley Fisher, Amanda French, William Gallentine, Ronald Goldberg, Kevin Hill, Sujay Kansagra, Sara Katsanis, Joanne Kurtzberg, Jeffrey Marcus, Marie McDonald, Mohammed Mikati, Stephen Miller, Amy Murtha, Yezmin Perilla, Carolyn Pizoli, Todd Purves, Sherry Ross, Edward Smith, and John Wiener

Subjects
Male, 0301 basic medicine, Movement disorders, Task Force for Neonatal Genomics, Contracture/genetics, Neurodegenerative, Bioinformatics, Neurodevelopmental Disorders/genetics, Infantile, Medical and Health Sciences, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Epilepsy/genetics, Spasms, Epilepsy, Spasms, Infantile/genetics, 0302 clinical medicine, R-Type, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Cation Transport Proteins, Genetics (clinical), Pediatric, Genetics & Heredity, Arthrogryposis, 0303 health sciences, Voltage-dependent calcium channel, Epileptic encephalopathy, Deciphering Developmental Disorders Study, Biological Sciences, Hypotonia, 3. Good health, CACNA1E, Genetic Variation/genetics, Child, Preschool, Neurological, Female, Megalencephaly/genetics, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Contracture, Adolescent, Dyskinesias/genetics, Biology, Article, arthrogryposis, 03 medical and health sciences, Genetics, medicine, Humans, Preschool, Calcium Channels, R-Type/genetics, 030304 developmental biology, Muscle contracture, Dyskinesias, business.industry, Calcium channel, Cation Transport Proteins/genetics, Neurosciences, Macrocephaly, Genetic Variation, Correction, Infant, medicine.disease, Human genetics, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, ion channel, calcium channel, Calcium Channels, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Item does not contain fulltext Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Published
2018

23. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Author

Sylvia Varland, Margaret Yoon, Jill A. Rosenfeld, Alison Gardner, Jennifer S. Beighley, Derek Lim, Ning Ma, Sonal Mahida, Magdalena Walkiewicz, Linyan Meng, Christopher Barnett, Claudia A. L. Ruivenkamp, Tjitske Kleefstra, Corrado Romano, Marie Shaw, Andrea M. Lewis, R. Frank Kooy, Avinash V. Dharmadhikari, Nicolette S. den Hollander, Elizabeth E. Palmer, Anke Van Dijck, Geert Vandeweyer, Emanuela Stracuzzi, Sébastien Küry, Kym M. Boycott, Stefania Giusto, Deepti Domingo, Asbjørg Stray-Pedersen, Fan Xia, Mauro Longoni, Grazia M.S. Mancini, Mohammad K. Eldomery, Yaping Yang, Zeynep Coban Akdemir, Evan E. Eichler, Raphael Bernier, Hanyin Cheng, Rebecca Willaert, Arie van Haeringen, Katherine Agre, Parul Jayakar, Sakkubai Naidu, Jozef Gecz, Lucinda Murray, Samantha K Rojas, Mathilde Nizon, Frances A. High, Joseph C. Wu, Richard E. Person, Gregory M. Cooper, Mark A. Corbett, Karin S. Kassahn, Thomas Arnesen, Rolph Pfundt, Erin Conboy, Vernon R. Sutton, Bronwyn Kerr, Holly A.F. Stessman, Ruth Armstrong, Sarah R. Crews, Marjon van Slegtenhorst, Jennifer E. Posey, James R. Lupski, Wendy K. Chung, Alan F. Rope, Jolanda H. Schieving, Robert Kleyner, Michael Parker, Gholson J. Lyon, Candice R. Finnila, Marjolijn J. Jongmans, Bert B.A. de Vries, and Clinical Genetics

Subjects
Male, 0301 basic medicine, Autism Spectrum Disorder, Messenger, N-terminal acetyltransferases (NATs), Neurodevelopmental disorder, Intellectual disability, N-terminal acetylation (NTA), Missense mutation, N-Terminal Acetyltransferase E, Child, N-Terminal Acetyltransferase A, Genetics (clinical), Genetics, Exons, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], congenital heart defects, Pedigree, Phenotype, Autism spectrum disorder, Female, Abnormalities, Haploinsufficiency, Multiple, Ogden syndrome, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Adolescent, autism, Saccharomyces cerevisiae, Biology, Cell Line, 03 medical and health sciences, Report, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, RNA, Messenger, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic Variation, medicine.disease, neurodevelopmental disorder, Ogden Syndrome, 030104 developmental biology, NAA10, Gene Expression Regulation, NatA complex, Mutation, RNA, Autism, Human medicine, NAA15
Abstract

Item does not contain fulltext N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Published
2018

24. 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

25. A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

Author

Susan Brammah, Honey Nagakura, Christopher T. Gordon, Laurence Hubert, Andrea M. Lewis, Renee Carroll, Richard H. Scott, Alexandrine Garrigue, Melanie Leffler, Jozef Gecz, Michael Field, Lucinda Murray, Sarah Risen, Seema R. Lalani, Marie Shaw, Geneviève de Saint Basile, Augusto Rendon, Raman Kumar, Tracy Dudding-Byth, LaDonna Immken, Patrick Nitschké, Arnold Munnich, Jeanne Amiel, Mark J. Cowley, Judy Spies, Bronwyn Kerr, Myriam Oufadem, Nina Powell-Hamilton, Claude Besmond, John D. Pollard, Emma Kivuva, Christine Bole-Feysot, William G. Newman, Jill A. Rosenfeld, Elizabeth E. Palmer, Jessica Tusi, Allison Tam, Richard Webster, Francesca Filippini, Marlène Rio, André E. Minoche, and Fan Xia

Subjects
0301 basic medicine, Central Nervous System, media_common.quotation_subject, Nonsense, Limb Deformities, Congenital, Neurocognitive Disorders, Bioinformatics, 03 medical and health sciences, Exon, Report, Intellectual Disability, Intellectual disability, Peripheral Nervous System, Genetics, medicine, Journal Article, Missense mutation, Humans, Craniofacial, Gene, Genetics (clinical), media_common, business.industry, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Codon, Nonsense, Peripheral nervous system, business, Mandibulofacial Dysostosis
Abstract

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

Published
2017

26. Oculo-auriculo-vertebral spectrum: Clinical and molecular analysis of 51 patients

Author

Rachel Hart, Fabiana Ramos, Helen Kingston, Rachel Scholey, Ana Beleza-Meireles, Jorge M. Saraiva, Luís Pires, Jill Clayton-Smith, Dian Donnai, Isabel M. Carreira, Ronnie Wright, Bronwyn Kerr, William G. Newman, Tracy A Briggs, Renata Nunes Oliveira, Kay Metcalfe, Jill E. Urquhart, Joaquim Sá, Lina Ramos, Cláudia F. Reis, May Tassabehji, Elizabete Cunha, and Margarida Venâncio

Subjects
Heart Defects, Congenital, Male, Pediatrics, medicine.medical_specialty, Hearing loss, Developmental Disabilities, Goldenhar syndrome, Branchial arch, Goldenhar Syndrome, Genetics, medicine, Humans, Abnormalities, Multiple, Eye Abnormalities, Family history, Craniofacial, Genetics (clinical), Hernia, Diaphragmatic, Comparative Genomic Hybridization, business.industry, Brain, Ear, General Medicine, Anatomy, medicine.disease, Spine, Hemifacial microsomia, Developmental disorder, Etiology, Female, medicine.symptom, business
Abstract

Introduction Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210 ) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. Methods We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. Results Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. Discussion In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).

Published
2015

27. A Study of the Clinical and Radiological Features in a Cohort of 93 Patients with a COL2A1 Mutation Causing Spondyloepiphyseal Dysplasia Congenita or a Related Phenotype

Author

Jill Clayton-Smith, Mariet W. Elting, Rutger A.J. Nievelstein, Linda Goodwin, Andreas Zankl, Paul Coucke, Paulien A. Terhal, Susan Price, Anne Dieux, Valérie Cormier-Daire, Eva J J Verver, Louise C. Wilson, Edward S. Tobias, Sahar Mansour, Niels Thomas Hertel, Maaike Vreeburg, Johanna C. Herkert, Emma Wakeling, Nicolette S. den Hollander, Elizabeth Thompson, Bronwyn Kerr, Marleen Simon, Nine V A M Knoers, Hanne Hove, Mohnish Suri, Tessa Homfray, Frances Elmslie, Raoul C.M. Hennekam, Muriel Holder-Espinasse, Jane A. Hurst, Sarah F. Smithson, André Mégarbané, Yasemin Alanay, Melissa Lees, Vedat Topsakal, Annick Raas-Rothschild, Marianne Rohrbach, Allan M. Lund, Barbara Schroeter, Hermine E. Veenstra-Knol, Regina C. Betz, Johanna M. van Hagen, Annick Toutain, Geert Mortier, Paula van Dommelen, Alison Male, Andrew Green, Kristien Hoornaert, Ernie M.H.F. Bongers, Annemarie H. van der Hout, Albert David, Goeran Anneren, Martine Le Merrer, Jenneke van den Ende, Esther Kinning, Carlo Marcelis, Surgical clinical sciences, Ear, nose & throat, Acibadem University Dspace, Clinical Genetics, Human genetics, Other Research, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Human Genetics

Subjects
Male, Hypermetropia, DNA Mutational Analysis, Review, Gene, Osteochondrodysplasias/congenital, Spondyloepiphyseal dysplasia, Genetics(clinical), Child, SEDC, COL2A1 gene, Bronchomalacia, Atlantoaxial dislocation, Pierre Robin syndrome, Osteotomy, Scoliosis, Health, Cleft palate, Spondyloepiphyseal dysplasia congenita, II COLLAGEN, Cohort studies, Hip arthroplasty, SKELETAL DYSPLASIA, Procollagen, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, COL2A1, Glycine, Major clinical study, Osteochondrodysplasias, Behavioural Changes, SDG 3 - Good Health and Well-being, Genetics, spondyloepiphyseal dysplasia, Humans, Genotype phenotype correlation, Collagen Type II, Aged, Tracheomalacia, Infant, medicine.disease, Otorhinolaryngology, DEFECT, Collagen disorder, School child, Human medicine, mutation, MYELOPATHY, Pediatrics, Amino acid substitution, Spondyloperipheral dysplasia, LS - Life Style, surgery, Tracheostomy, Serine, Myopia, Missense mutation, RETINAL-DETACHMENT, Non-U.S. Gov't, Genetics (clinical), Heterozygosity, Research Support, Non-U.S. Gov't, Odontoid Hypoplasia, Middle Aged, genotype-phenotype, Clubfoot, Phenotype, KNIEST-DYSPLASIA, young adult, Female, medicine.symptom, Collagen Type II/genetics, Healthy Living, radiography, Adult, EXPRESSION, Retina detachment, Child, preschool, Adolescent, review, Population research, Genotype-phenotype, Research Support, Short stature, Hearing impairment, Multiple epiphyseal dysplasia, Kniest dysplasia, CARTILAGE, Coxa vara, Journal Article, medicine, Gene mutation, Disease severity, Genetic Association Studies, business.industry, Gestational age, Respiratory distress, Mutational analysis, GENE, Clinical feature, Dysplasia, Aspartic acid, ELSS - Earth, Life and Social Sciences, Healthy for Life, business
Abstract

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n=64), others having SEMD (n=5), Kniest dysplasia (n=7), spondyloperipheral dysplasia (n=2), or Torrance-like dysplasia (n=2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders. (c) 2015 Wiley Periodicals, Inc.

Published
2015

29. Further Clinical Delineation of the MEF2C Haploinsufficiency Syndrome: Report on New Cases and Literature Review of Severe Neurodevelopmental Disorders Presenting with Seizures, Absent Speech, and Involuntary Movements

Author

Irena Vrečar, William Reardon, Bronwyn Kerr, Elizabeth A. Jones, Sofia Douzgou, J A Innes, Helen Kingston, and Jill Clayton-Smith

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, business.industry, Genetic counseling, 030105 genetics & heredity, Audiology, medicine.disease, Hypotonia, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, MEF2C Gene, Pediatrics, Perinatology and Child Health, Speech delay, Intellectual disability, medicine, medicine.symptom, Differential diagnosis, business, Haploinsufficiency, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract

Mutations in the MEF2C (myocyte enhancer factor 2) gene have been established as a cause for an intellectual disability syndrome presenting with seizures, absence of speech, stereotypic movements, hypotonia, and limited ambulation. Phenotypic overlap with Rett's and Angelman's syndromes has been noted. Following the first reports of 5q14.3q15 microdeletions encompassing the MEF2C gene, further cases with point mutations and partial gene deletions of the MEF2C gene have been described. We present the clinical phenotype of our cohort of six patients with MEF2C mutations and compare our findings with previously reported patients as well as with a growing number of genetic conditions presenting with a severe neurodevelopmental, Rett-like, phenotype. We aim to add to the current knowledge of the natural history of the “MEF2C haploinsufficiency syndrome” as well as of the differential diagnosis, clinical management, and genetic counseling in this diagnostically challenging group of patients.

Published
2017

30. Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1

Author

Tabib Dabir, Roman A. Laskowski, Shelagh Joss, Jenny Morton, Janet M. Thornton, Caroline F. Wright, Jochem M. G. Evers, Jill Clayton-Smith, Miranda Splitt, Meriel McEntagart, Dragana Josifova, Bronwyn Kerr, Alison Kraus, Audrey Smith, Mohnish Suri, Kate Baker, Sinéad O’Brien, Baker, Kate [0000-0003-2986-0584], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, syntaxin‐binding protein 1, syntaxin-binding protein 1, Protein domain, Population, Biology, Munc18, 03 medical and health sciences, 0302 clinical medicine, Exome Aggregation Consortium, genomics, Genetics, STXBP1, Missense mutation, Genetics(clinical), protein structure, education, Exome, Gene, Molecular Biology, Genetics (clinical), Loss function, education.field_of_study, Epilepsy, Original Articles, 3. Good health, 030104 developmental biology, epilepsy, Original Article, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract

Background Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype–phenotype correlations. Methods We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (ExAC). Results Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype–phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP1 pathogenic variants did not present with very early-onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. Conclusion Variants across STXBP1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study.

Published
2017

31. 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

32. Recent developments in neurofibromatoses and RASopathies: Management, diagnosis and current and future therapeutic avenues

Author

Susan M Huson, Said Farschtschi, Juha Peltonen, Thijs van der Vaart, Vincent M. Riccardi, Emma Burkitt-Wright, Luis F. Parada, Eric Legius, Michael A. Patton, Bronwyn Kerr, David H. Gutmann, Katherine A. Rauen, D. Gareth Evans, Rosalie E. Ferner, Martin Zenker, David Viskochil, Miikka Vikkula, Nancy Ratner, C. Oliver Hanemann, Meena Upadhyaya, and Neurosciences

Subjects
Legius syndrome, medicine.medical_specialty, business.industry, Translational research, RASopathy, ta3111, medicine.disease, Bioinformatics, humanities, Article, Endocrinology, Germline mutation, Costello syndrome, Internal medicine, Genetics, medicine, Noonan syndrome, Neurofibromatosis, business, Genetics (clinical), Neurofibromatoses
Abstract

Neurofibromatosis type 1 (NF1) was the first RASopathy and is now one of many RASopathies that are caused by germline mutations in genes that encode components of the Ras/mito- gen-activated protein kinase (MAPK) pathway. Their common underlying pathogenetic etiology causes significant overlap in phenotypic features which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormali- ties, and a predisposition to cancer. The proceedings from the symposium “Recent Developments in Neurofibromatoses (NF) and RASopathies: Management, Diagnosis and Current and Future Therapeutic Avenues” chronicle this timely and topical clinical translational research symposium. The overarching goal was to bring together clinicians, basic scientists, physician- scientists, advocate leaders, trainees, students and individuals with Ras pathway syndromes to discuss the most state-of-the-art basic science and clinical issues in an effort to spark collabo- rations directed towards the best practices and therapies for individuals with RASopathies.

Published
2014

33. NovelKDM6A(UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2)

Author

D. Beysen, Deborah J. Shears, Siddharth Banka, Bernard Grisart, Grazia M.S. Mancini, Damien Lederer, S. Bunstone, Ravi Savarirayan, Dian Donnai, Valérie Benoit, Shane McKee, E. Jenkins, Bronwyn Kerr, Isabelle Maystadt, E. Howard, Susan M. White, Ronald D. Cohn, H. Stewart, and I C Lloyd

Subjects
Hypertrichosis, Genetics, Mutation, Mutation rate, Pediatrics, medicine.medical_specialty, Biology, medicine.disease_cause, medicine.disease, Short stature, Hypotonia, Exon, medicine, Missense mutation, medicine.symptom, Kabuki syndrome, Genetics (clinical)
Abstract

We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ-line missense and splice-site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome (KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate-severe in boys but mild-moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some patients.

Published
2014

34. Leri’s pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassingGDF6andSDC2and provides insight into systemic sclerosis pathogenesis

Author

Andreas Superti-Furga, Siddharth Banka, Günhan Erdem, Helen Kingston, Bronwyn Kerr, William G. Newman, Sabrya Carim, Michelle Bottomley, Ariane L. Herrick, Sheila Unger, Sarah B. Daly, Cay M. Kielty, Jane Worthington, Jade Harris, Dian Donnai, Wyatt W. Yue, Catherine L.R. Merry, Holly Ennis, Jill E. Urquhart, and Stuart A. Cain

Subjects
business.industry, Immunology, medicine.disease, Stiff skin syndrome, Phenotype, General Biochemistry, Genetics and Molecular Biology, Minor allele frequency, Pathogenesis, Rheumatology, GDF6, Acromicric dysplasia, medicine, Immunology and Allergy, Missense mutation, Myhre syndrome, business
Abstract

ObjectivesLeri’s pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis.Methods and resultsWhole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes,GDF6andSDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missenseSDC2variant, p.Ser71Thr, could confer protection against disease (p−5).ConclusionsOur work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing ‘TGF-β-pathies’ group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill–Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protectiveSDC2variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.

Published
2014

35. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein

Author

Natalie J. Prescott, Elizabeth Bentley, Paul Rutland, Brandon J. Wainwright, John Nelson, Bronwyn Kerr, Susan M. Darling, Vile Makela, Robert F. Mueller, Shalini Jadeja, Christine Francannet, Lesley M McGregor, Antonio Perez-Aytes, Emma Roberts, André Mégarbané, Jason Hopkins, Sofia Vrontou, Adrian S. Woolf, Alison Shaw, Nicole Philip, Nicola Smart, Robin M. Winter, Georges Chalepakis, Peter J. Scambler, and Catherine Roberts

Subjects
Male, Cryptophthalmos, DNA Mutational Analysis, Molecular Sequence Data, Mice, Inbred Strains, Locus (genetics), Biology, Frameshift mutation, Mice, Blister, Genetics, medicine, Animals, Humans, Fraser syndrome, Extracellular Matrix Proteins, Base Sequence, Genetic heterogeneity, DNA, Denys-Drash Syndrome, medicine.disease, Molecular biology, Phenotype, Mice, Mutant Strains, Pedigree, Disease Models, Animal, Mutation testing, FRAS1, Female, Chromosomes, Human, Pair 4
Abstract

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects(1). Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse(2), which has been associated with mutations in at least five loci including bl(3). As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.

Published
2016

36. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis

Author

Houman Ashrafian, Charles Redwood, Edward Blair, Marisa Oliveira, Bronwyn Kerr, Hugh Watkins, John Broxholme, Ingegerd Östman-Smith, and Anthony P. Salmon

Subjects
Candidate gene, Heart disease, DNA Mutational Analysis, Molecular Sequence Data, Biology, medicine.disease_cause, Electrocardiography, Genetic model, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Amino Acid Sequence, Protein kinase A, Molecular Biology, Genetics (clinical), Mutation, Sequence Homology, Amino Acid, Hypertrophic cardiomyopathy, AMPK, Exons, General Medicine, Cardiomyopathy, Hypertrophic, medicine.disease, Introns, Pedigree, cardiovascular system, Protein Kinases
Abstract

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the gamma(2) subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.

Published
2016

37. MLL2mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome

Author

Sarju G. Mehta, Siddharth Banka, John Tolmie, Bronwyn Kerr, Emma Howard, Dian Donnai, Katherine Lachlan, Sancha Bunstone, Kate Chandler, Shane McKee, and Ana Lisa Taylor Tavares

Subjects
Sanger sequencing, Genetics, Mutation, Point mutation, Disease, Biology, medicine.disease_cause, Bioinformatics, medicine.disease, Phenotype, symbols.namesake, Gene duplication, Genotype, medicine, symbols, Kabuki syndrome, Genetics (clinical)
Abstract

Kabuki syndrome (KS) is a rare multi-system disorder that can result in a variety of congenital malformations, typical dysmorphism and variable learning disability. It is caused by MLL2 point mutations in the majority of the cases and, rarely by deletions involving KDM6A. Nearly one third of cases remain unsolved. Here, we expand the known genetic basis of KS by presenting five typical patients with the condition, all of whom have novel MLL2 mutation types- two patients with mosaic small deletions, one with a mosaic whole-gene deletion, one with a multi-exon deletion and one with an intragenic multi-exon duplication. We recommend MLL2 dosage studies for all patients with typical KS, where traditional Sanger sequencing fails to identify mutations. The prevalence of such MLL2 mutations in KS may be comparable with deletions involving KDM6A. These findings may be helpful in understanding the mutational mechanism of MLL2 and the disease mechanism of KS.

Published
2012

38. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Author

Sixto García-Miñaur, Ratna Veeramachaneni, Susan Price, Nicola Ragge, Kay Metcalfe, Graeme C.M. Black, Christopher P. Bennett, William Reardon, Alex Magee, Soo Mi Park, Jill Clayton-Smith, Nicole Revencu, Bruce Castle, Christine Oley, Wayne W.K. Lam, Vivienne McConnell, Deirdre E. Donnelly, Deepthi De Silva, Andrew E. Fry, I. Karen Temple, Judith A. Goodship, Helen Kingston, Gunnar Houge, Fiona Stewart, Sally J. Davies, Frances Elmslie, John Tolmie, Sancha Bunstone, Harinder Gill, Emma Howard, Shehla Mohammed, Moira Blyth, Michael Parker, Emma Hobson, Dian Donnai, Michael Wright, Kate Chandler, Amanda L. Collins, Susann Schweiger, Katherine Lachlan, Alex Henderson, Richard Gibbons, Siren Berland, Audrey Smith, Sally Ann Lynch, Pradeep Vasudevan, Bronwyn Kerr, Richard Fisher, Meriel McEntagart, Jenny Morton, Siddharth Banka, Yanick J. Crow, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, and UCL - (SLuc) Centre de génétique médicale UCL

Subjects
Biology, medicine.disease_cause, Article, Cohort Studies, Genetic Heterogeneity, Exon, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Epigenetics, Genetics (clinical), Mutation, Genetic heterogeneity, Cancer, Sequence Analysis, DNA, medicine.disease, Hematologic Diseases, Phenotype, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Face, Female, Kabuki syndrome
Abstract

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients. © 2012 Macmillan Publishers Limited All rights reserved.

Published
2011

39. Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome

Author

Sanjeev S. Bhaskar, Shehla Mohammed, Sahar Mansour, Janine Smith, Tim Thomas, Jill Clayton-Smith, Beverley Anderson, Dian Donnai, Leslie G. Biesecker, Alan Fryer, Ruth Day, Philip Smith, Shane McKee, Bronwyn Kerr, Kate Chandler, Małgorzata Krajewska-Walasek, Sally Ann Lynch, Anne K. Voss, May Tassabehji, Graeme C.M. Black, James O'Sullivan, Sarah B. Daly, and Elizabeth Sweeney

Subjects
Adult, Heart Defects, Congenital, Joint Instability, Male, Mice, Transgenic, Biology, Blepharophimosis, Polymorphism, Single Nucleotide, symbols.namesake, Exon, Mice, INDEL Mutation, Intellectual Disability, Report, medicine, Congenital Hypothyroidism, Genetics, Animals, Humans, Abnormalities, Multiple, Exome, Genetics(clinical), Child, Gene, Genetics (clinical), Exome sequencing, Histone Acetyltransferases, Sanger sequencing, Regulation of gene expression, Chromosomes, Human, Pair 10, Facies, Gene Expression Regulation, Developmental, medicine.disease, Microarray Analysis, Chromatin, Codon, Nonsense, symbols, Genitopatellar syndrome, Female, Metabolism, Inborn Errors
Abstract

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.

Published
2011
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40. Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

Author

Judith Allanson, Klaudiusz Luczak, Hans Gerd Kehl, Gabriele Krüger, Marco Tartaglia, Martin Zenker, Thomas Neumann, Beate Albrecht, Hartmut Peters, Rohan Laurie, Kate Gibson, Vera M. Kalscheuer, Giovanni Neri, Viviana Cordeddu, Luciana Musante, Timm O. Goecke, Andreas Tzschach, Maria Hoeltzenbein, Bronwyn Kerr, Ines Kavamura, Maria M. Sasiadek, Jacqueline A. Noonan, Univ Erlangen Nurnberg, Univ Hosp Munster, Childrens Hosp Eastern Ontario, Universidade Federal de São Paulo (UNIFESP), Royal Manchester Childrens Hosp, Univ Cattolica, Univ Kentucky, Ist Super Sanita, Royal Childrens Hosp, Max Planck Inst Mol Genet, Univ Hosp Rostock, Univ Hosp Dusseldorf, Univ Hosp Essen, Wroclaw Med Univ, Mater Pathol Serv, and Univ Hosp Charite

Subjects
cardio-facio-cutaneous, Adult, Male, inorganic chemicals, endocrine system, Adolescent, Heart Diseases, MAP Kinase Signaling System, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, Giant Cells, Skin Diseases, LEOPARD Syndrome, Article, cardio-facio-cutaneous syndrome, Cohort Studies, Genetics, medicine, Noonan syndrome, Humans, Abnormalities, Multiple, Child, Genetics (clinical), Mutation, business.industry, multiple giant cell lesions, Noonan-like/multiple giant cell lesion syndrome, Noonan Syndrome, Syndrome, medicine.disease, Osteochondrodysplasia, PTPN11, Phenotype, Giant cell, ras Proteins, Cancer research, SOS1, Female, Nooan syndrome, KRAS, business, Nooan syndrome, cardio-facio-cutaneous, RAS-MAPK signaling cascade
Abstract

German Research Foundation (DFG) Telethon-Italy Associazione ONLUS Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. the NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. in a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype-phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects. Univ Erlangen Nurnberg, Inst Human Genet, Univ Hosp Erlangen, D-8520 Erlangen, Germany Univ Hosp Munster, Dept Human Genet, Munster, Germany Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada Universidade Federal de São Paulo, São Paulo, Brazil Royal Manchester Childrens Hosp, Manchester M27 1HA, Lancs, England Univ Cattolica, Inst Med Genet, Rome, Italy Univ Kentucky, Coll Med, Div Cardiol, Dept Pediat, Lexington, KY USA Ist Super Sanita, Dipartimento Biol Cellulare & Neurosci, I-00161 Rome, Italy Royal Childrens Hosp, Genet Hlth Queensland, Herston, Qld, Australia Max Planck Inst Mol Genet, Berlin, Germany Univ Hosp Rostock, Med Genet Unit, Dept Pediat, Rostock, Germany Univ Hosp Dusseldorf, Dept Human Genet, Dusseldorf, Germany Univ Hosp Munster, Dept Pediat Cardiol, Munster, Germany Univ Hosp Essen, Dept Human Genet, Essen, Germany Wroclaw Med Univ, Dept Maxilla Facial Surg, Wroclaw, Poland Wroclaw Med Univ, Dept Genet, Wroclaw, Poland Mater Pathol Serv, Brisbane, Qld, Australia Univ Hosp Charite, Dept Med Genet, Berlin, Germany Universidade Federal de São Paulo, São Paulo, Brazil German Research Foundation (DFG): Ze 524/4-1 Telethon-Italy: GGP07115 Web of Science

Published
2008

41. Severe neonatal manifestations of Costello syndrome

Author

M T Soo, Ben Tang, Jenny Shorto, Graeme C.M. Black, Carole Brewer, Stephen Ts Lam, Daniel Ng, Nora Shannon, Ivan Fm Lo, and Bronwyn Kerr

Subjects
Alveolar capillary dysplasia, medicine.medical_specialty, education.field_of_study, business.industry, Population, Cardiomyopathy, medicine.disease, Gastroenterology, Pericardial effusion, Endocrinology, Costello syndrome, Internal medicine, Genetics, medicine, Missense mutation, HRAS, Differential diagnosis, business, education, Genetics (clinical)
Abstract

Background: Costello syndrome (CS) is due to mutations in HRAS, with the commonest mutation being c.34G>A (p.G12S), found in most patients in all the published series1,3-7. A small number of less common mutations have been reported. Population studied: HRAS mutation analysis has been undertaken in 74 predominantly British patients with a possible diagnosis of Costello syndrome. A HRAS mutation was found in 27 patients, 15 of whom have been previously reported3. Phenotype analysis: Four cases had an unusually severe phenotype, associated in three cases with two unusual mutations, c.35G>A, p.G12D in two cases and c.34G>T, p.G12C in the other. Hypoglycaemia, renal abnormalities, severe early cardiomyopathy, congenital lung and airway abnormalities, pleural and pericardial effusion, chylous ascites and pulmonary lymphangectasia are confirmed as part of the clinical spectrum seen in CS. A lung pathology resembling alveolar capillary dysplasia is reported in one case. Conclusion: These cases illustrate that the diagnosis of Costello syndrome may be difficult in the newborn period, and should be considered in the differential diagnosis of the sick newborn infant with multi-system disease. Study of more cases will be required to establish if there is a definite association between severe disease and less common mutations.

Published
2007

42. A New Subtype of Brachydactyly Type B Caused by Point Mutations in the Bone Morphogenetic Protein Antagonist NOGGIN

Author

Katarina Lehmann, C. Reissner, S. Irgang, Klaus W. Kjaer, Fatma Silan, Petra Seemann, Andrew O.M. Wilkie, Susanne Morlot, S. Kjaergaard, Stefan Mundlos, Timm O. Goecke, Maurice J. Mahoney, and Bronwyn Kerr

Subjects
Male, Models, Molecular, Biology, Bone morphogenetic protein, Fingers, 03 medical and health sciences, 0302 clinical medicine, Report, Genetics, medicine, Humans, Point Mutation, Genetics(clinical), Noggin, Receptor, Genetics (clinical), Loss function, 030304 developmental biology, Orphan receptor, 0303 health sciences, Point mutation, Brachydactyly, ROR2, Toes, medicine.disease, Pedigree, Cell biology, body regions, Bone Morphogenetic Proteins, Female, Carrier Proteins, Hand Deformities, Congenital, 030217 neurology & neurosurgery
Abstract

Wilkie, Andrew/0000-0002-2972-5481; Seemann, Petra/0000-0002-6056-6669; Dathe, Katarina/0000-0002-8674-5817 WOS: 000248540400018 PubMed: 17668388 (B) under bar rachy (d) under bar actyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the ma ority of patients n a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36p, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BD13, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system. Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface. Wellcome TrustWellcome Trust

Published
2007

43. An Absence of Cutaneous Neurofibromas Associated with a 3-bp Inframe Deletion in Exon 17 of the NF1 Gene (c.2970-2972 delAAT): Evidence of a Clinically Significant NF1 Genotype-Phenotype Correlation

Author

S. Giovannini, Susan M Huson, D G R Evans, Nadia Chuzhanova, Rachel K. Hachen, J. P. Van Biervliet, Hua Li, A. Barnicoat, David A. Stevenson, Dave Viskochil, M. Davies, Conxi Lázaro, Darius J. Adams, E. Howard, Vincent M. Riccardi, Nicholas Stuart Tudor Thomas, Sian Wyn Griffiths, Diana Baralle, Bronwyn Kerr, Peter D. Turnpenny, Meena Upadhyaya, Claudia Consoli, Lucy Side, Ludwine Messiaen, Eric Haan, Mary Ella M Pierpont, and P. Wallace

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Neurofibromatosis 1, Skin Neoplasms, Adolescent, Genotype, Biology, medicine.disease_cause, Article, Exon, Genetics, medicine, Humans, Neurofibroma, Genetics(clinical), Child, Genetics (clinical), Watson syndrome, Sequence Deletion, Legius syndrome, Mutation, Neurofibromin 1, Exons, Sequence Analysis, DNA, Middle Aged, medicine.disease, Phenotype, Pedigree, nervous system diseases, biology.protein, Female
Abstract

Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA--ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.

Published
2007

44. Patient complaints as predictors of patient safety incidents

Author

Bronwyn Kerr, Helen L Kroening, Iain Yardley, and J. Bruce

Subjects
Medicine (General), business.industry, patient experience, communication, Applied Mathematics, General Mathematics, government.form_of_government, Delayed treatment, medicine.disease, Patient identification, Patient safety, Qualitative analysis, Consumer engagement, R5-920, Patient experience, government, patient safety, Early warning system, Medicine, Medical emergency, Public aspects of medicine, RA1-1270, business, Incident report, consumer engagement
Abstract

Patients remain an underused resource in efforts to improve quality and safety in healthcare, despite evidence that they can provide valuable insights into the care they receive. This study aimed to establish whether high-level patient safety incidents (HLIs) were predictable from preceding complaints, enabling complaints to be used to prevent HLIs. For this study complaints received from November 2011 through June 2012 and HLI incident reports from April through September 2012 were examined. Complaints and HLIs were categorised according to location or specialty and the themes they included. Data were analysed to look for correlations between number of complaints and HLIs in a given area. A qualitative analysis was carried out to determine whether any complaints contained information that, if acted upon earlier, could have prevented later HLIs. In the data a total of 52 complaints and 16 HLIs were included. No correlation was established between location of HLIs and complaints. Complaints commonly focused on staff attitude, diagnostic problems and delayed treatment. HLIs most often arose from failure to recognise a patient’s deterioration and escalate appropriately or incorrect patient identification. Most HLIs were not preceded by similar complaints. However, in two instances complaints did signpost future HLIs. Patient complaints can highlight specific risks to patient safety and act as an early warning system. There is a need to devise reliable means of identifying the minority of complaints that do precede serious incidents.

Published
2015

45. Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease

Author

Rachel, Lennon, Helen M, Stuart, Agnieszka, Bierzynska, Michael J, Randles, Bronwyn, Kerr, Katherine A, Hillman, Gauri, Batra, Joanna, Campbell, Helen, Storey, Frances A, Flinter, Ania, Koziell, Gavin I, Welsh, Moin A, Saleem, Nicholas J A, Webb, and Adrian S, Woolf

Subjects
Adult, Collagen Type IV, Male, Siblings, Kidney Glomerulus, Inheritance Patterns, Nephrotic syndrome, Whole exome sequencing, Infant, Nephritis, Hereditary, urologic and male genital diseases, Severity of Illness Index, Pedigree, Myosin Type I, Child, Preschool, Mutation, Genetics, Humans, Female, Original Article, COL4A5, MYO1E, Child, Alport syndrome
Abstract

Background Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. Methods We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. Results We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E, p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein–protein interactions to intracellular myosin 1E. Conclusions COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non-COL4 ‘podocyte gene’ mutations in XLAS when clinical nephropathy is more severe than expected for an individual’s age and sex.

Published
2014

46. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases

Author

Nicole Philip, A. De Sandre-Giovannoli, M. A. Delrue, Alain Verloes, Dian Donnai, Carole Brewer, Graeme C.M. Black, Willie Reardon, James O'Sullivan, Raoul C.M. Hennekam, Ben Tang, Fiona Stewart, Benoit Arveiler, M. Stef, Didier Lacombe, Sabine Sigaudy, O. B. Eden, E. M'Cann, Nicolas Lévy, Hélène Cavé, I. Burgelin, O. Quarell, Bronwyn Kerr, Christopher P. Bennett, Marche M, Rahat Perveen, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatric Genetics

Subjects
Adult, Adolescent, Genotype, DNA Mutational Analysis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Biology, Malignancy, medicine.disease_cause, Proto-Oncogene Mas, Diagnosis, Differential, Proto-Oncogene Proteins p21(ras), Costello syndrome, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, HRAS, Child, Genetics (clinical), Mutation, Noonan Syndrome, Intracellular Signaling Peptides and Proteins, Infant, Syndrome, medicine.disease, Phenotype, Child, Preschool, Failure to thrive, Noonan syndrome, Female, Original Article, Protein Tyrosine Phosphatases, medicine.symptom
Abstract

Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. Methods: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. Results: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. Conclusions: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

Published
2005

47. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients

Author

Alison Kerr, Kay D. MacDermot, Yanick J. Crow, David Neil Cooper, Rachel Butler, Angus John Clarke, Peter Huppke, J. Horn, G. Hermon, Sharon D. Whatley, Franco Laccone, Alex Magee, Willie Reardon, David Ravine, David J. Bunyan, A. Donaldson, E. Sweeney, Bronwyn Kerr, R. A. Smith, Julie Evans, Daniela T. Pilz, Stephen Davies, Hayley Archer, L. P. Lazarou, Julian R. Sampson, and Z. Miedzybrodzka

Subjects
Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Adolescent, Methyl-CpG-Binding Protein 2, DNA Mutational Analysis, Gene Dosage, Rett syndrome, Biology, Gene dosage, MECP2, Cohort Studies, Molecular genetics, Rett Syndrome, Genetics, medicine, Humans, Atypical Rett syndrome, Genetic Testing, Multiplex ligation-dependent probe amplification, Child, Genetics (clinical), Chromosome Aberrations, Breakpoint, Gene rearrangement, medicine.disease, Child, Preschool, Female, Letter to JMG
Abstract

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Published
2005

48. BRCA1/2 predictive testing: a study of uptake in two centres

Author

L. Brooks, Rachel Belk, Audrey Ardern-Jones, Fiona Lalloo, D. Gareth Evans, A Shenton, Ingrid Ambus, David Craufurd, Rosalind A. Eeles, Bronwyn Kerr, and Fiona Lennard

Subjects
Male, Proband, medicine.medical_specialty, Time Factors, Genetic counseling, Genes, BRCA2, Genes, BRCA1, MEDLINE, Genetic Counseling, Family communication, Genetics, Humans, Medicine, Genetic Testing, Predictive testing, Genetics (clinical), Genetic testing, Attending clinic, medicine.diagnostic_test, business.industry, Ovary cancer, United Kingdom, Pedigree, Family medicine, Mutation, Female, business
Abstract

Differences in reported uptake of genetic testing for mutations in BRCA1 and BRCA2 can largely be accounted for by different methodologies and by studying research vs nonresearch families. In our joint study of 75 nonresearch families from two UK centres in which at least 3 years had elapsed since the initial proband had been informed of the availability of testing, only 45 and 34% of eligible individuals from Manchester and London, respectively, had come forward for counselling. Final uptake rates using a non-proactive approach were 53 and 29% for women and 11-12% for men, but the figure among those attending clinic was 73 and 62%, respectively. Unlike previous studies, we did not find that uptake had stabilised after a year with 25% of those being tested more than 2 years after the family was informed, and several delaying a considerable time between genetics appointments. We believe that the particularly low uptake even of counselling in men may need to be addressed by improving family communication or providing information sheets for family members to disseminate.

Published
2004

49. The clinical picture of the Börjeson-Forssman-Lehmann syndrome in males and heterozygous females with PHF6 mutations

Author

Martin Wright, HE Hoyme, Martin B. Delatycki, Bronwyn Kerr, Tjitske Kleefstra, Michael Partington, Gillian Turner, Markus Grompe, Karen M. Lower, AK Lampe, Jozef Gecz, B. B. A. De Vries, SL White, Susan Schelley, Barbara Cox, and JC Smith

Subjects
medicine.medical_specialty, Microcephaly, Pediatrics, Coarse facial features, business.industry, Macrocephaly, Börjeson-Forssman-Lehmann syndrome, medicine.disease, Short stature, Endocrinology, Gynecomastia, Internal medicine, Failure to thrive, Genetics, medicine, medicine.symptom, business, Skewed X-inactivation, Genetics (clinical)
Abstract

The usual description of the Borjeson-Forssman-Lehmann syndrome (BFLS) is that of a rare, X-linked, partially dominant condition with severe intellectual disability, epilepsy, microcephaly, coarse facial features, long ears, short stature, obesity, gynecomastia, tapering fingers, and shortened toes. Recently, mutations have been identified in the PHF6 gene in nine families with this syndrome. The clinical history and physical findings in the affected males reveal that the phenotype is milder and more variable than previously described and evolves with age. Generally, in the first year, the babies are floppy, with failure to thrive, big ears, and small external genitalia. As schoolboys, the picture is one of learning problems, moderate short stature, with emerging truncal obesity and gynecomastia. Head circumferences are usually normal, and macrocephaly may be seen. Big ears and small genitalia remain. The toes are short and fingers tapered and malleable. In late adolescence and adult life, the classically described heavy facial appearance emerges. Some heterozygous females show milder clinical features such as tapering fingers and shortened toes. Twenty percent have significant learning problems, and 95% have skewed X inactivation. We conclude that this syndrome may be underdiagnosed in males in their early years and missed altogether in isolated heterozygous females.

Published
2004

50. Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes

Author

Zaid Afawi, Bobby P. C. Koeleman, Christina A.G. Bergqvist, Carolien G.F. de Kovel, Vijayakumar Jayaraman, Sonal Desai, Eric D. Marsh, Holly Dubbs, Ethan M. Goldberg, Tilman Polster, Eva H. Brilstra, Laura K. Conlin, Bronwyn Kerr, Ramakrishnan Rajagopalan, Johannes R. Lemke, Hande Cagaylan, Manuela Pendziwiat, Uluç Yiş, Ingo Borggraefe, Ingo Helbig, Allan Bayat, Sudha Kilaru Kessler, Nienke E. Verbeek, Siddharth Srivastava, Marie-José van den Boogaardt, Sakkubai Naidu, Carol J Saunders, Isabelle Thiffault, Rikke S. Møller, Karl-Martin Klein, Hiltrud Muhle, Susanna Plugge, Martin B. Rook, Steffen Syrbe, and Bryan L Krok

Subjects
0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Genotype, Mutation, Missense, Genome-wide association study, 03 medical and health sciences, symbols.namesake, Young Adult, Genotype-phenotype distinction, Shab Potassium Channels, medicine, Journal Article, Missense mutation, Humans, Child, Preschool, Original Investigation, Sanger sequencing, Massive parallel sequencing, business.industry, Genetic disorder, Brain, Electroencephalography, medicine.disease, Magnetic Resonance Imaging, Epileptic spasms, 030104 developmental biology, Phenotype, Neurodevelopmental Disorders, Child, Preschool, Mutation, symbols, Female, Neurology (clinical), Missense, business, Genome-Wide Association Study
Abstract

Importance: Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients.Objectives: To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations.Design, Setting, and Participants: This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project.Main Outcomes and Measures: The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one.Results: Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region.Conclusions and Relevance: De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

Published
2017

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