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1. Exploring the Frontier: The Human Microbiome’s Role in Rare Childhood Neurological Diseases and Epilepsy

Author: Newell Belnap, Keri Ramsey, Sophia T. Carvalho, Lexi Nearman, Hannah Haas, Matt Huentelman, and Keehoon Lee
Subjects: epilepsy, microbiome, gut–brain axis, drug-resistance epilepsy, rare childhood disease, microbiome-epilepsy, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Emerging research into the human microbiome, an intricate ecosystem of microorganisms residing in and on our bodies, reveals that it plays a pivotal role in maintaining our health, highlighting the potential for microbiome-based interventions to prevent, diagnose, treat, and manage a myriad of diseases. The objective of this review is to highlight the importance of microbiome studies in enhancing our understanding of rare genetic epilepsy and related neurological disorders. Studies suggest that the gut microbiome, acting through the gut–brain axis, impacts the development and severity of epileptic conditions in children. Disruptions in microbial composition can affect neurotransmitter systems, inflammatory responses, and immune regulation, which are all critical factors in the pathogenesis of epilepsy. This growing body of evidence points to the potential of microbiome-targeted therapies, such as probiotics or dietary modifications, as innovative approaches to managing epilepsy. By harnessing the power of the microbiome, we stand to develop more effective and personalized treatment strategies for children affected by this disease and other rare neurological diseases.
Published: 2024
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2. Family and caregiver perspectives on gene therapy for Rett syndrome

Author: Keri Ramsey, Madison LaFleur, Kiana Robinson, Mark Borgstrom, Ashley Ryan, Vinodh Narayanan, and Valerie Schaibley
Subjects: Rett syndrome, Gene therapy, Risk, Caregiver, Medicine, Genetics, QH426-470
Abstract: Introduction: Rett syndrome (RTT) is a neurodevelopmental disorder that primarily affects females and can result in cognitive impairment, seizures, spasticity, breathing problems, gastrointestinal issues, motor impairment, and behavioral concerns. Gene therapy may be a potential treatment in the future as clinical trials are underway. Aim: This study evaluates the attitudes and opinions of family members and caregivers of patients with RTT towards gene therapy using a mixed-method approach. Methods: Sixty-six caregivers of individuals with RTT completed an online survey asking about their previous experience in research and questions about their understanding of gene therapy, their expectations, as well as their hopes and concerns for treating RTT. Ten respondents also participated in online focus groups, which were evaluated using thematic analysis. Results: Overall, most participants (95.5 %) had heard about gene therapy. More than half of the respondents (68.2 %) reported being somewhat knowledgeable about gene therapy, and 18.2 % reported no understanding of gene therapy. When asked the highest level of risk they would accept when enrolling the individual with Rett syndrome in a gene therapy clinical trial, 47.7 % stated they would accept a low risk, and 7.7 % indicated they would accept a high risk. In the focus groups, individuals discussed barriers to gene therapy, their hopes and concerns regarding gene therapy treatment, and how they would like to receive information about future research and therapies. Participants had concerns about possible side effects of gene therapy, including physical and mental harm, a potential decrease in quality of life, whether individuals with RTT would want to “change who they are,” and the irreversibility of the treatment. Conclusion: Although most participants have heard about gene therapy, many caregivers would only accept a low risk when considering gene therapy for the individual with RTT. This could be in part due to concerns about side effects and potential harm to the patient as well as anticipated barriers related to cost and accessibility to appropriate follow-up care. Understanding caregiver opinions is important in setting goals and evaluating the success of current studies, identifying and addressing barriers to trials and treatment, and in the development and implementation of educational resources for gene therapy in RTT.
Published: 2024
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3. Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author: Margot A. Cousin, Emma L. Veale, Nikita R. Dsouza, Swarnendu Tripathi, Robyn G. Holden, Maria Arelin, Geoffrey Beek, Mir Reza Bekheirnia, Jasmin Beygo, Vikas Bhambhani, Martin Bialer, Stefania Bigoni, Cyrus Boelman, Jenny Carmichael, Thomas Courtin, Benjamin Cogne, Ivana Dabaj, Diane Doummar, Laura Fazilleau, Alessandra Ferlini, Ralitza H. Gavrilova, John M. Graham, Tobias B. Haack, Jane Juusola, Sarina G. Kant, Saima Kayani, Boris Keren, Petra Ketteler, Chiara Klöckner, Tamara T. Koopmann, Teresa M. Kruisselbrink, Alma Kuechler, Laëtitia Lambert, Xénia Latypova, Robert Roger Lebel, Magalie S. Leduc, Emanuela Leonardi, Andrea M. Lewis, Wendy Liew, Keren Machol, Samir Mardini, Kirsty McWalter, Cyril Mignot, Julie McLaughlin, Alessandra Murgia, Vinodh Narayanan, Caroline Nava, Sonja Neuser, Mathilde Nizon, Davide Ognibene, Joohyun Park, Konrad Platzer, Céline Poirsier, Maximilian Radtke, Keri Ramsey, Cassandra K. Runke, Maria J. Guillen Sacoto, Fernando Scaglia, Marwan Shinawi, Stephanie Spranger, Ee Shien Tan, John Taylor, Anne-Sophie Trentesaux, Filippo Vairo, Rebecca Willaert, Neda Zadeh, Raul Urrutia, Dusica Babovic-Vuksanovic, Michael T. Zimmermann, Alistair Mathie, and Eric W. Klee
Subjects: KCNK9 imprinting syndrome, TASK3 channel, Neurodevelopmental disorder, Electrophysiology, Computational protein modeling, Medicine, Genetics, QH426-470
Abstract: Abstract Background Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.
Published: 2022
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4. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

Author: Michael A. Levy, David B. Beck, Kay Metcalfe, Sofia Douzgou, Sivagamy Sithambaram, Trudie Cottrell, Muhammad Ansar, Jennifer Kerkhof, Cyril Mignot, Marie-Christine Nougues, Boris Keren, Hannah W. Moore, Renske Oegema, Jacques C. Giltay, Marleen Simon, Richard H. van Jaarsveld, Jessica Bos, Mieke van Haelst, M. Mahdi Motazacker, Elles M. J. Boon, Gijs W. E. Santen, Claudia A. L. Ruivenkamp, Marielle Alders, Teresa Romeo Luperchio, Leandros Boukas, Keri Ramsey, Vinodh Narayanan, G. Bradley Schaefer, Roberto Bonasio, Kimberly F. Doheny, Roger E. Stevenson, Sidharth Banka, Bekim Sadikovic, and Jill A. Fahrner
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.
Published: 2021
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5. Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases

Author: Francisco M. De La Vega, Shimul Chowdhury, Barry Moore, Erwin Frise, Jeanette McCarthy, Edgar Javier Hernandez, Terence Wong, Kiely James, Lucia Guidugli, Pankaj B. Agrawal, Casie A. Genetti, Catherine A. Brownstein, Alan H. Beggs, Britt-Sabina Löscher, Andre Franke, Braden Boone, Shawn E. Levy, Katrin Õunap, Sander Pajusalu, Matt Huentelman, Keri Ramsey, Marcus Naymik, Vinodh Narayanan, Narayanan Veeraraghavan, Paul Billings, Martin G. Reese, Mark Yandell, and Stephen F. Kingsmore
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Background Clinical interpretation of genetic variants in the context of the patient’s phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease. Here we assess the diagnostic performance of Fabric GEM, a new, AI-based, clinical decision support tool for expediting genome interpretation. Methods We benchmarked GEM in a retrospective cohort of 119 probands, mostly NICU infants, diagnosed with rare genetic diseases, who received whole-genome or whole-exome sequencing (WGS, WES). We replicated our analyses in a separate cohort of 60 cases collected from five academic medical centers. For comparison, we also analyzed these cases with current state-of-the-art variant prioritization tools. Included in the comparisons were trio, duo, and singleton cases. Variants underpinning diagnoses spanned diverse modes of inheritance and types, including structural variants (SVs). Patient phenotypes were extracted from clinical notes by two means: manually and using an automated clinical natural language processing (CNLP) tool. Finally, 14 previously unsolved cases were reanalyzed. Results GEM ranked over 90% of the causal genes among the top or second candidate and prioritized for review a median of 3 candidate genes per case, using either manually curated or CNLP-derived phenotype descriptions. Ranking of trios and duos was unchanged when analyzed as singletons. In 17 of 20 cases with diagnostic SVs, GEM identified the causal SVs as the top candidate and in 19/20 within the top five, irrespective of whether SV calls were provided or inferred ab initio by GEM using its own internal SV detection algorithm. GEM showed similar performance in absence of parental genotypes. Analysis of 14 previously unsolved cases resulted in a novel finding for one case, candidates ultimately not advanced upon manual review for 3 cases, and no new findings for 10 cases. Conclusions GEM enabled diagnostic interpretation inclusive of all variant types through automated nomination of a very short list of candidate genes and disorders for final review and reporting. In combination with deep phenotyping by CNLP, GEM enables substantial automation of genetic disease diagnosis, potentially decreasing cost and expediting case review.
Published: 2021
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6. Generation of an iPSC line from a Pontocerebellar Hypoplasia 1B patient harboring a homozygous c.395 A > C mutation in EXOSC3 along with a family matched control

Author: Ben N. Stansfield, Sampath Rangasamy, Keri Ramsey, May Khanna, and Jared M. Churko
Subjects: Biology (General), QH301-705.5
Abstract: Pontocerebellar Hypoplasia 1B (PCH1B) is a severe autosomal recessive neurological disorder that is associated with mutations in the exosome complex component RRP40 (EXOSC3) gene. We generated and characterized an iPSC line from an individual with PCH1B that harbors a recessive homozygous c.395 A > C mutation in EXOSC3 and a family matched control from the probands unaffected mother. Each iPSC line presents with normal morphology and karyotype and express high levels of pluripotent markers. UAZTi009-A and UAZTi011-A are capable of directed differentiation and can be used as a vital experimental tool to study the development of PCH1B.
Published: 2022
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7. Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders

Author: Eric Frankel, Avijit Podder, Megan Sharifi, Roshan Pillai, Newell Belnap, Keri Ramsey, Julius Dodson, Pooja Venugopal, Molly Brzezinski, Lorida Llaci, Brittany Gerald, Gabrielle Mills, Meredith Sanchez-Castillo, Chris D. Balak, Szabolcs Szelinger, Wayne M. Jepsen, Ashley L. Siniard, Ryan Richholt, Marcus Naymik, Isabelle Schrauwen, David W. Craig, Ignazio S. Piras, Matthew J. Huentelman, Nicholas J. Schork, Vinodh Narayanan, and Sampathkumar Rangasamy
Subjects: Rett syndrome, atypical RTT syndrome, Rett-syndrome-like phenotype, methyl-CpG-binding protein 2, neurodevelopmental disorders, overlapping phenotype, Cytology, QH573-671
Abstract: Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to have an overlapping neurological phenotype with RTT but are lacking a mutation in a gene that causes classical or atypical RTT can be described as having a ‘Rett-syndrome-like phenotype (RTT-L). Here, we report eight patients from our cohort diagnosed as having RTT-L who carry mutations in genes unrelated to RTT. We annotated the list of genes associated with RTT-L from our patient cohort, considered them in the light of peer-reviewed articles on the genetics of RTT-L, and constructed an integrated protein–protein interaction network (PPIN) consisting of 2871 interactions connecting 2192 neighboring proteins among RTT- and RTT-L-associated genes. Functional enrichment analysis of RTT and RTT-L genes identified a number of intuitive biological processes. We also identified transcription factors (TFs) whose binding sites are common across the set of RTT and RTT-L genes and appear as important regulatory motifs for them. Investigation of the most significant over-represented pathway analysis suggests that HDAC1 and CHD4 likely play a central role in the interactome between RTT and RTT-L genes.
Published: 2023
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8. Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

Author: Jinhong Wie, Apoorva Bharthur, Morgan Wolfgang, Vinodh Narayanan, Keri Ramsey, C4RCD Research Group, Kimberly Aranda, Qi Zhang, Yandong Zhou, and Dejian Ren
Subjects: Science
Abstract: The sodium-leak channel NALCN controls the resting membrane potentials of neurons. Here, the authors identified two subunits of NALCN, UNC80 and UNC79. Domains in UNC80, which are mutated in individuals with intellectual disability, interact to achieve the dendritic localization of NALCN complex.
Published: 2020
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9. Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Author: Yu-Ri Lee, Kamal Khan, Kim Armfield-Uhas, Sujata Srikanth, Nicola A. Thompson, Mercedes Pardo, Lu Yu, Joy W. Norris, Yunhui Peng, Karen W. Gripp, Kirk A. Aleck, Chumei Li, Ed Spence, Tae-Ik Choi, Soo Jeong Kwon, Hee-Moon Park, Daseuli Yu, Won Do Heo, Marie R. Mooney, Shahid M. Baig, Ingrid M. Wentzensen, Aida Telegrafi, Kirsty McWalter, Trevor Moreland, Chelsea Roadhouse, Keri Ramsey, Michael J. Lyons, Cindy Skinner, Emil Alexov, Nicholas Katsanis, Roger E. Stevenson, Jyoti S. Choudhary, David J. Adams, Cheol-Hee Kim, Erica E. Davis, and Charles E. Schwartz
Subjects: Science
Abstract: Armfield X-linked disability (XLID) disorder has previously been linked to a locus in Xq28. Here, the authors report rare missense variants in FAM50A at Xq28, show that FAM50A interacts with the spliceosome, and that mis-splicing is enriched in knockout zebrafish suggesting it is a spliceosomopathy.
Published: 2020
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10. Progressive cerebellar atrophy caused by heterozygous TECPR2 mutations

Author: Keri Ramsey, Newell Belnap, Anna Bonfitto, Wayne Jepsen, Marcus Naymik, Meredith Sanchez‐Castillo, David W. Craig, Szabolcs Szelinger, Matthew J. Huentelman, Vinodh Narayanan, and Sampath Rangasamy
Subjects: Genetics, QH426-470
Published: 2022
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11. GABRG2 Variants Associated with Febrile Seizures

Author: Ciria C. Hernandez, Yanwen Shen, Ningning Hu, Wangzhen Shen, Vinodh Narayanan, Keri Ramsey, Wen He, Liping Zou, and Robert L. Macdonald
Subjects: GABAARs, febrile seizures, mutations, Microbiology, QR1-502
Abstract: Febrile seizures (FS) are the most common form of epilepsy in children between six months and five years of age. FS is a self-limited type of fever-related seizure. However, complicated prolonged FS can lead to complex partial epilepsy. We found that among the GABAA receptor subunit (GABR) genes, most variants associated with FS are harbored in the γ2 subunit (GABRG2). Here, we characterized the effects of eight variants in the GABAA receptor γ2 subunit on receptor biogenesis and channel function. Two-thirds of the GABRG2 variants followed the expected autosomal dominant inheritance in FS and occurred as missense and nonsense variants. The remaining one-third appeared as de novo in the affected probands and occurred only as missense variants. The loss of GABAA receptor function and dominant negative effect on GABAA receptor biogenesis likely caused the FS phenotype. In general, variants in the GABRG2 result in a broad spectrum of phenotypic severity, ranging from asymptomatic, FS, genetic epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome individuals. The data presented here support the link between FS, epilepsy, and GABRG2 variants, shedding light on the relationship between the variant topological occurrence and disease severity.
Published: 2023
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12. Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Author: Aleksandra Siekierska, Hannah Stamberger, Tine Deconinck, Stephanie N. Oprescu, Michèle Partoens, Yifan Zhang, Jo Sourbron, Elias Adriaenssens, Patrick Mullen, Patrick Wiencek, Katia Hardies, Jeong-Soo Lee, Hoi-Khoanh Giong, Felix Distelmaier, Orly Elpeleg, Katherine L. Helbig, Joseph Hersh, Sedat Isikay, Elizabeth Jordan, Ender Karaca, Angela Kecskes, James R. Lupski, Reka Kovacs-Nagy, Patrick May, Vinodh Narayanan, Manuela Pendziwiat, Keri Ramsey, Sampathkumar Rangasamy, Deepali N. Shinde, Ronen Spiegel, Vincent Timmerman, Sarah von Spiczak, Ingo Helbig, C4RCD Research Group, AR working group of the EuroEPINOMICS RES Consortium, Sarah Weckhuysen, Christopher Francklyn, Anthony Antonellis, Peter de Witte, and Peter De Jonghe
Subjects: Science
Abstract: tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.
Published: 2019
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13. Adenosine triphosphate binding cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro

Author: Wayne M. Jepsen, Matthew De Both, Ashley L. Siniard, Keri Ramsey, Ignazio S. Piras, Marcus Naymik, Adrienne Henderson, and Matthew J. Huentelman
Subjects: abcc1, app, amyloid, alzheimer's disease, timp3, cd38, Science, Biology (General), QH301-705.5
Abstract: The organic anion transporter Adenosine triphosphate binding cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood–brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the amyloid precursor protein (APP), likely via indirect modulation of alpha-, beta- and gamma-secretase activity.
Published: 2021
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14. Author Correction: Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

Author: Michael A. Levy, David B. Beck, Kay Metcalfe, Sofia Douzgou, Sivagamy Sithambaram, Trudie Cottrell, Muhammad Ansar, Jennifer Kerkhof, Cyril Mignot, Marie-Christine Nougues, Boris Keren, Hannah W. Moore, Renske Oegema, Jacques C. Giltay, Marleen Simon, Richard H. van Jaarsveld, Jessica Bos, Mieke van Haelst, M. Mahdi Motazacker, Elles M. J. Boon, Gijs W. E. Santen, Claudia A. L. Ruivenkamp, Marielle Alders, Teresa Romeo Luperchio, Leandros Boukas, Keri Ramsey, Vinodh Narayanan, G. Bradley Schaefer, Roberto Bonasio, Kimberly F. Doheny, Roger E. Stevenson, Siddharth Banka, Bekim Sadikovic, and Jill A. Fahrner
Subjects: Medicine, Genetics, QH426-470
Published: 2021
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15. The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants [version 1; referees: 2 approved]

Author: Katrina Tatton-Brown, Anna Zachariou, Chey Loveday, Anthony Renwick, Shazia Mahamdallie, Lise Aksglaede, Diana Baralle, Daniela Barge-Schaapveld, Moira Blyth, Mieke Bouma, Jeroen Breckpot, Beau Crabb, Tabib Dabir, Valerie Cormier-Daire, Christine Fauth, Richard Fisher, Blanca Gener, David Goudie, Tessa Homfray, Matthew Hunter, Agnete Jorgensen, Sarina G. Kant, Cathy Kirally-Borri, David Koolen, Ajith Kumar, Anatalia Labilloy, Melissa Lees, Carlo Marcelis, Catherine Mercer, Cyril Mignot, Kathryn Miller, Katherine Neas, Ruth Newbury-Ecob, Daniela T. Pilz, Renata Posmyk, Carlos Prada, Keri Ramsey, Linda M. Randolph, Angelo Selicorni, Deborah Shears, Mohnish Suri, I. Karen Temple, Peter Turnpenny, Lionel Val Maldergem, Vinod Varghese, Hermine E. Veenstra-Knol, Naomi Yachelevich, Laura Yates, Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Research Study, Deciphering Developmental Disorders (DDD) Study, and Nazneen Rahman
Subjects: Medicine, Science
Abstract: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS
Published: 2018
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16. Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability [version 1; referees: 2 approved]

Author: Erika Banuelos, Keri Ramsey, Newell Belnap, Malavika Krishnan, Chris Balak, Szabolcs Szelinger, Ashley L. Siniard, Megan Russell, Ryan Richholt, Matt De Both, Ignazio Piras, Marcus Naymik, Ana M. Claasen, Sampathkumar Rangasamy, Matthew J. Huentelman, David W. Craig, Philippe M. Campeau, Vinodh Narayanan, and Isabelle Schrauwen
Subjects: Medical Genetics, Medicine, Science
Abstract: Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy
Published: 2017
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17. Case Report: Compound heterozygous nonsense mutations in TRMT10A are associated with microcephaly, delayed development, and periventricular white matter hyperintensities [version 1; referees: 2 approved]

Author: Mohan Narayanan, Keri Ramsey, Theresa Grebe, Isabelle Schrauwen, Szabolcs Szelinger, Matthew Huentelman, David Craig, Vinodh Narayanan, and C4RCD Research Group
Subjects: Diabetes & Obesity, Genomics, Medicine, Science
Abstract: Microcephaly is a fairly common feature observed in children with delayed development, defined as head circumference less than 2 standard deviations below the mean for age and gender. It may be the result of an acquired insult to the brain, such prenatal or perinatal brain injury (congenital infection or hypoxic ischemic encephalopathy), or be a part of a genetic syndrome. There are over 1000 conditions listed in OMIM (Online Mendelian Inheritance in Man) where microcephaly is a key finding; many of these are associated with specific somatic features and non-CNS anomalies. The term primary microcephaly is used when microcephaly and delayed development are the primary features, and they are not part of another recognized syndrome. In this case report, we present the clinical features of siblings (brother and sister) with primary microcephaly and delayed development, and subtle dysmorphic features. Both children had brain MRI studies that showed periventricular and subcortical T2/FLAIR hyperintensities, without signs of white matter volume loss, and no parenchymal calcifications by CT scan. The family was enrolled in a research study for whole exome sequencing of probands and parents. Analysis of variants determined that the children were compound heterozygotes for nonsense mutations, c.277C>T (p.Arg93*) and c.397C>T (p.Arg133*), in the TRMT10A gene. Mutations in this gene have only recently been reported in children with microcephaly and early onset diabetes mellitus. Our report adds to current knowledge of TRMT10A related neurodevelopmental disorders and demonstrates imaging findings suggestive of delayed or abnormal myelination of the white matter in this disorder. Accurate diagnosis through genomic testing, as in the children described here, allows for early detection and management of medical complications, such as diabetes mellitus.
Published: 2015
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18. A Frame-Shift Mutation in CAV1 Is Associated with a Severe Neonatal Progeroid and Lipodystrophy Syndrome.

Author: Isabelle Schrauwen, Szabolcs Szelinger, Ashley L Siniard, Ahmet Kurdoglu, Jason J Corneveaux, Ivana Malenica, Ryan Richholt, Guy Van Camp, Matt De Both, Shanker Swaminathan, Mari Turk, Keri Ramsey, David W Craig, Vinodh Narayanan, and Matthew J Huentelman
Subjects: Medicine, Science
Abstract: A 3-year-old female patient presenting with an unknown syndrome of a neonatal progeroid appearance, lipodystrophy, pulmonary hypertension, cutis marmorata, feeding disorder and failure to thrive was investigated by whole-genome sequencing. This revealed a de novo, heterozygous, frame-shift mutation in the Caveolin1 gene (CAV1) (p.Phe160X). Mutations in CAV1, encoding the main component of the caveolae in plasma membranes, cause Berardinelli-Seip congenital lipodystrophy type 3 (BSCL). Although BSCL is recessive, heterozygous carriers either show a reduced phenotype of partial lipodystrophy, pulmonary hypertension, or no phenotype. To investigate the pathogenic mechanisms underlying this syndrome in more depth, we performed next generation RNA sequencing of peripheral blood, which showed several dysregulated pathways in the patient that might be related to the phenotypic progeroid features (apoptosis, DNA repair/replication, mitochondrial). Secondly, we found a significant down-regulation of known Cav1 interaction partners, verifying the dysfunction of CAV1. Other known progeroid genes and lipodystrophy genes were also dysregulated. Next, western blotting of lysates of cultured fibroblasts showed that the patient shows a significantly decreased expression of wild-type CAV1 protein, demonstrating a loss-of-function mutation, though her phenotype is more severe that other heterozygotes with similar mutations. This phenotypic variety could be explained by differences in genetic background. Indications for this are supported by additional rare variants we found in AGPAT2 and LPIN1 lipodystrophy genes. CAV1, AGPAT2 and LPIN1 all play an important role in triacylglycerol (TAG) biosynthesis in adipose tissue, and the defective function in different parts of this pathway, though not all to the same extend, could contribute to a more severe lipoatrophic phenotype in this patient. In conclusion, we report, for the first time, an association of CAV1 dysfunction with a syndrome of severe premature aging and lipodystrophy. This may contribute to a better understanding of the aging process and pathogenic mechanisms that contribute to premature aging.
Published: 2015
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19. Variation in the large-scale organization of gene expression levels in the hippocampus relates to stable epigenetic variability in behavior.

Author: Mark D Alter, Daniel B Rubin, Keri Ramsey, Rebecca Halpern, Dietrich A Stephan, L F Abbott, and Rene Hen
Subjects: Medicine, Science
Abstract: Despite sharing the same genes, identical twins demonstrate substantial variability in behavioral traits and in their risk for disease. Epigenetic factors-DNA and chromatin modifications that affect levels of gene expression without affecting the DNA sequence-are thought to be important in establishing this variability. Epigenetically-mediated differences in the levels of gene expression that are associated with individual variability traditionally are thought to occur only in a gene-specific manner. We challenge this idea by exploring the large-scale organizational patterns of gene expression in an epigenetic model of behavioral variability.To study the effects of epigenetic influences on behavioral variability, we examine gene expression in genetically identical mice. Using a novel approach to microarray analysis, we show that variability in the large-scale organization of gene expression levels, rather than differences in the expression levels of specific genes, is associated with individual differences in behavior. Specifically, increased activity in the open field is associated with increased variance of log-transformed measures of gene expression in the hippocampus, a brain region involved in open field activity. Early life experience that increases adult activity in the open field also similarly modifies the variance of gene expression levels. The same association of the variance of gene expression levels with behavioral variability is found with levels of gene expression in the hippocampus of genetically heterogeneous outbred populations of mice, suggesting that variation in the large-scale organization of gene expression levels may also be relevant to phenotypic differences in outbred populations such as humans. We find that the increased variance in gene expression levels is attributable to an increasing separation of several large, log-normally distributed families of gene expression levels. We also show that the presence of these multiple log-normal distributions of gene expression levels is a universal characteristic of gene expression in eurkaryotes. We use data from the MicroArray Quality Control Project (MAQC) to demonstrate that our method is robust and that it reliably detects biological differences in the large-scale organization of gene expression levels.Our results contrast with the traditional belief that epigenetic effects on gene expression occur only at the level of specific genes and suggest instead that the large-scale organization of gene expression levels provides important insights into the relationship of gene expression with behavioral variability. Understanding the epigenetic, genetic, and environmental factors that regulate the large-scale organization of gene expression levels, and how changes in this large-scale organization influences brain development and behavior will be a major future challenge in the field of behavioral genomics.
Published: 2008
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20. Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Author: Ashish R Deshwar, Cheryl Cytrynbaum, Harsha Murthy, Jessica Zon, David Chitayat, Jonathan Volpatti, Ruth Newbury-Ecob, Sian Ellard, Hana Lango Allen, Emily P Yu, Ramil Noche, Suzi Walker, Stephen W Scherer, Sonal Mahida, Christopher M Elitt, Gaël Nicolas, Alice Goldenberg, Pascale Saugier-Veber, Francois Lecoquierre, Ivana Dabaj, Hannah Meddaugh, Michael Marble, Kim M Keppler-Noreuil, Lucy Drayson, Kristin W Barañano, Anna Chassevent, Katie Agre, Pascaline Létard, Frederic Bilan, Gwenaël Le Guyader, Annie Laquerrière, Keri Ramsey, Lindsay Henderson, Lauren Brady, Mark Tarnopolsky, Matthew Bainbridge, Jennifer Friedman, Yline Capri, Larissa Athayde, Fernando Kok, Juliana Gurgel-Giannetti, Luiza L P Ramos, Susan Blaser, James J Dowling, Rosanna Weksberg, Deshwar, Ashish R [0000-0002-9239-3846], Scherer, Stephen W [0000-0002-8326-1999], Nicolas, Gaël [0000-0001-9391-7800], Dabaj, Ivana [0000-0002-2324-1208], Dowling, James J [0000-0002-3984-4169], and Apollo - University of Cambridge Repository
Subjects: brain calcifications, CLDN5, blood brain barrier, Neurology (clinical)
Abstract: The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood–brain barrier and impaired neuronal function.
Published: 2023

21. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Author: Newell Belnap, Bert B.A. de Vries, Austin Larson, Rolph Pfundt, Marijke R. Wevers, Valérie Benoit, Markus Zweier, Pascal Joset, Anita Rauch, Angela Bahr, Jeroen Mourmans, Patricia G Wheeler, Or Gozani, Marisa V. Andrews, Monica H. Wojcik, Didier Lacombe, Sarah Grotto, Marwan Shinawi, Lot Snijders Blok, Conny M. A. van Ravenswaaij-Arts, Keri Ramsey, Deepanwita Sengupta, Mariarosaria Lang-Muritano, Isabelle Maystadt, Katharina Steindl, Paolo Zanoni, Antonio Vitobello, Geoffroy Delplancq, Katrin Õunap, Tania Attié-Bitach, Heinrich Sticht, Giulia Petrilli, Laurence Faivre, Vassilis Tsatsaris, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: 0301 basic medicine, In silico, Biology, Article, REGION, 03 medical and health sciences, ROGERS-DANKS-SYNDROME, 0302 clinical medicine, Missense mutation, HISTONE H3, Gene, Genetics (clinical), Loss function, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DELETION, DEFECTS, Methylation, Phenotype, LYSINE 36, 030104 developmental biology, Molecular mechanism, WOLF-HIRSCHHORN-SYNDROME, 030217 neurology & neurosurgery, Function (biology), Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype., Genetics in Medicine, 23 (8)
Published: 2021
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22. CSNK2B

Author: Judith Bluvstein, Suneeta Madan-Khetarpal, Daniel Groepper, Theodore Sheehan, Michael J. Lyons, Louise Bier, Julie Fleischer, Annapurna Poduri, Lynn Pais, Pascal Joset, Elena Infante, Evan H. Baugh, David Goldstein, Tristan T. Sands, Katharina Steindl, Pim Suwannarat, Cyril Mignot, Boris Keren, Matthew J. Ferber, Laura Schultz-Rogers, Natalie Lippa, Linda Hasadsri, Vinodh Narayanan, Maureen S. Mulhern, Alejandra Vasquez, Claudia A. L. Ruivenkamp, Marleen Simon, Susan M. White, Vimla Aggarwal, Eric W. Klee, Kristine K. Bachman, Lindsay C. Burrage, Caroline Nava, Nicholas Stong, Neil A. Hanchard, Josephine S.C. Chong, Anita Rauch, Renee Bend, Erin L. Heinzen, Sulagna Kushary, Marije Koopmans, Marissa S. Ellingson, Keri Ramsey, Raymond Yeh, Michelle E. Ernst, Ellen van Binsbergen, Sarah S. Barnett, Amanda Thomas, Kristin G. Monaghan, Eva H. Brilstra, Magalie S. Leduc, Weimin Bi, Jennifer A. Lee, Cigdem I. Akman, Sophie Mathieu, Andrea H. Seeley, Grazia M. S. Mancini, and Clinical Genetics
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, CK2, Developmental Disabilities, Epilepsies, Myoclonic, Status epilepticus, casein kinase II, Article, MSNE, 03 medical and health sciences, Broad spectrum, Epilepsy, Young Adult, 0302 clinical medicine, Status Epilepticus, Intellectual Disability, Intellectual disability, medicine, Humans, Exome, Generalized epilepsy, Age of Onset, generalized epilepsy, Child, Exome sequencing, business.industry, Genetic Variation, Infant, medicine.disease, Young age, 030104 developmental biology, myoclonic status epilepticus, Phenotype, Neurology, Child, Preschool, Mutation, myoclonic seizures, Epilepsy, Generalized, Female, Neurology (clinical), medicine.symptom, Epilepsy severity, business, 030217 neurology & neurosurgery
Abstract: CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.
Published: 2021

23. Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord

Author: Parith Wongkittichote, Tae‐Ik Choi, Oc‐Hee Kim, Kacie Riley, Dwight Koeberl, Vinodh Narayanan, Keri Ramsey, Chris Balak, Charles E. Schwartz, Anna Maria Cueto‐Gonzalez, Francina Munell Casadesus, Cheol‐Hee Kim, and Marwan S. Shinawi
Subjects: Genetics, Genetics (clinical)
Abstract: ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142TA (p.Tyr48Asn), c.558GA (p.Met186Ile) and c.602CT (p.Pro201Leu), and a nonsense variant, c.618CA (p.Cys206*). Two variants were previously reported : a nonsense variant c.199CT (p.Arg67*) and a splice site variant (c.225+5GA). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.
Published: 2022

24. Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Author: Charles E. Schwartz, Emil Alexov, Jyoti S. Choudhary, Sujata Srikanth, Joy Norris, Keri Ramsey, Lu Yu, David J. Adams, Yu-Ri Lee, Karen W. Gripp, Ed Spence, Cheol-Hee Kim, Aida Telegrafi, Roger E. Stevenson, Chelsea Roadhouse, Trevor Moreland, Tae Ik Choi, Soo Jeong Kwon, Hee Moon Park, Erica E. Davis, Ingrid M. Wentzensen, Won Do Heo, Kim Armfield-Uhas, Cindy Skinner, Nicholas Katsanis, Yunhui Peng, Kamal Khan, Mercedes Pardo, Kirsty McWalter, Shahid Mahmood Baig, Marie R. Mooney, Nicola A. Thompson, Michael J. Lyons, Chumei Li, Daseuli Yu, and Kirk Aleck
Subjects: 0301 basic medicine, Male, Molecular biology, General Physics and Astronomy, 030105 genetics & heredity, medicine.disease_cause, Transcriptome, Mice, RNA, Small Nuclear, Missense mutation, lcsh:Science, Child, Zebrafish, Genetics, Mutation, Multidisciplinary, Gene Expression Regulation, Developmental, RNA-Binding Proteins, Syndrome, Phenotype, Pedigree, DNA-Binding Proteins, Protein Transport, Child, Preschool, Female, Adult, Spliceosome, congenital, hereditary, and neonatal diseases and abnormalities, RNA Splicing, Science, Mutation, Missense, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Intellectual Disability, Developmental biology, medicine, Animals, Humans, Family, RNA, Messenger, Cell Nucleus, Alternative splicing, General Chemistry, Zebrafish Proteins, biology.organism_classification, Xq28, nervous system diseases, 030104 developmental biology, Mental Retardation, X-Linked, NIH 3T3 Cells, Spliceosomes, lcsh:Q, Neuroscience
Abstract: Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3′ alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development., Armfield X-linked disability (XLID) disorder has previously been linked to a locus in Xq28. Here, the authors report rare missense variants in FAM50A at Xq28, show that FAM50A interacts with the spliceosome, and that mis-splicing is enriched in knockout zebrafish suggesting it is a spliceosomopathy.
Published: 2020

25. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author: Ashley N. Sigafoos, Salima El Chehadeh, Marcia C. Willing, Ela Akay, Florian Cherik, Anne-Marie E. Goyette, Vinodh Narayanan, Diane Masser-Frye, Catherine Karimov, Rhonda E. Schnur, Rebekah Bressi, Rhys H. Thomas, Gary D. Clark, Tina Barbaro-Dieber, Jill A. Rosenfeld, Carlos A. Bacino, Maria J. Guillen Sacoto, Laura Russell, Kristin Lindstrom, Caroline Schluth-Bolard, Xia Wang, Yvonne Hilhorst-Hofstee, Marcelo Vargas, Zehua Zhu, Ash Zawerton, Boris Keren, Mariëtte J.V. Hoffer, Isabelle Marey, Alice Poisson, Daphné Lehalle, Maries Joseph, Gaetan Lesca, Simon Zwolinski, Laurence Perrin, Rhoda Akilapa, Emilia K. Bijlsma, Christel Depienne, Amélie Piton, Claire G. Salter, Lucie Dupuis, Daryl A. Scott, Jolien S. Klein Wassink-Ruiter, Benjamin Cogné, Mathilde Nizon, Richard Chang, Kirsty McWalter, Myriam Srour, Perrine Charles, Anne-Claude Tabet, Natalie Canham, Sylvie Odent, Caroline Nava, Karl J. Clark, Elizabeth J. Bhoj, Jonathan Levy, Keri Ramsey, Yves Alembik, Lucia Ortega, Sophie Dupuis-Girod, Shoji Ichikawa, Christine Francannet, Marta Bertoli, Christèle Dubourg, Eric W. Klee, Ange-Line Bruel, Sebastien Moutton, Emily Fassi, Anthony Vandersteen, Abdul Haseeb, Antonina Wojcik, Patrick R. Blackburn, Lynne M. Bird, Patrick Rump, Véronique Lefebvre, Alma Kuechler, Sophie Nambot, Keren Machol, Cyril Mignot, Andreas Hartmann, Rossana Sanchez Russo, Erica H. Gerkes, Sylvie Jaillard, Roberto Mendoza-Londono, Trevor Cole, Pauline Monin, Cleveland Clinic, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, This research was funded in part by the Agence Nationale de la Recherche and European High-Functioning Autism Network (ANR EUHFAUTISM), the Assistance Publique–Hôpitaux de Paris (AP-HP), the Institut National de la Santé et de la Recherche Médicale (INSERM), the BioPsy labex (to Christel Depienne and C.N.) and the Association Française du Syndrome Gilles de la Tourette (AFSGT) to Christel Depienne. It was also funded by the Cleveland Clinic Lerner Research Institute (LRI Chair’s Innovative Research Award to V.L.), and by Harper’s Quest and the LAMSHF Syndrome Research Fund (donations to V.L.) and the Center for Individualized Medicine, Mayo Clinic. This study makes use of data generated by the DECIPHER community and the Deciphering Developmental Disorders (DDD) Study, which is funded by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network., We thank the patients and their families for their participation in this study, and the C4RCD Research Group (Newell Belnap, Amanda Courtright, Ana Claasen, David Craig, Matt Huentelman, Madison LaFleur, Sampathkumar Rangasamy, Ryan Richholt, Isabelle Schrauwen, Ashley L. Siniard, and Szabolics Szelinger) for providing clinical information on patient P18., Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Medizin, Haploinsufficiency, L-SOX5, VARIANTS, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics, Pediatric, Genetics & Heredity, 0303 health sciences, Pedigree, FAMILY, DNA-Binding Proteins, developmental delay, TRANSCRIPTION FACTORS, Phenotype, intellectual disability, Child, Preschool, missense variants, Female, SOXD Transcription Factors, Adult, EXPRESSION, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Mutation, Missense, autism, Cell fate determination, Biology, LONG FORM, SEQUENCE, Article, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, CARTILAGE, Intellectual Disability, medicine, Animals, Humans, Language Development Disorders, Genetic Predisposition to Disease, Preschool, Transcription factor, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, Human Genome, Infant, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, Deciphering Developmental Disorder Study, Mutation, Autism, epilepsy, Missense, 030217 neurology & neurosurgery, GENERATION
Abstract: International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
Published: 2020
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26. SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance

Author: Amélie Cordovado, Martina Schaettin, Médéric Jeanne, Veranika Panasenkava, Anne-Sophie Denommé-Pichon, Boris Keren, Cyril Mignot, Martine Doco-Fenzy, Lance Rodan, Keri Ramsey, Vinodh Narayanan, Julie R Jones, Eloise J Prijoles, Wendy G Mitchell, Jillian R Ozmore, Kali Juliette, Erin Torti, Elizabeth A Normand, Leslie Granger, Andrea K Petersen, Margaret G Au, Juliann P Matheny, Chanika Phornphutkul, Mary-Kathryn Chambers, Joaquín-Alejandro Fernández-Ramos, Eduardo López-Laso, Michael C Kruer, Somayeh Bakhtiari, Marcella Zollino, Manuela Morleo, Giuseppe Marangi, Davide Mei, Tiziana Pisano, Renzo Guerrini, Raymond J Louie, Anna Childers, David B Everman, Betrand Isidor, Séverine Audebert-Bellanger, Sylvie Odent, Dominique Bonneau, Brigitte Gilbert-Dussardier, Richard Redon, Stéphane Bézieau, Frédéric Laumonnier, Esther T Stoeckli, Annick Toutain, Marie-Laure Vuillaume, Jonchère, Laurent, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Zürich [Zürich] = University of Zurich (UZH), FHU TRANSLAD (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)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), The Translational Genomics Research Institute (TGen), The Greenwood Genetic Center, Keck School of Medicine [Los Angeles], University of Southern California (USC), Dartmouth Hitchcock Medical Center [Lebanon], Gillette Children's Specialty Healthcare [St Paul], GeneDx [Gaithersburg, MD, USA], Randall Children's Hospital [Portland], University of Kentucky (UK), Warren Alpert Medical School of Brown University, Rhode Island Hospital [Providence, RI, États-Unis], Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, Barrow Neurological Institute, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Università degli Studi di Firenze = University of Florence (UniFI), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Morvan - CHRU de Brest (CHU - BREST ), 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 ), CHU Pontchaillou [Rennes], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Funding for HUGODIMS (Western France exome-based trio approach project to identifygenes involved in intellectual disability) was supported by a grant from the French Ministryof Health and from the Health Regional Agency from Poitou-Charentes [HUGODIMS, 2013,RC14_0107]. [A.C.] is a research student recipient of a grant from the University of Tours., Cordovado, Amélie, Schaettin, Martina, Jeanne, Médéric, Panasenkava, Veranika, Denommé-Pichon, Anne-Sophie, Keren, Bori, Mignot, Cyril, Doco-Fenzy, Martine, Rodan, Lance, Ramsey, Keri, Narayanan, Vinodh, Jones, Julie R, Prijoles, Eloise J, Mitchell, Wendy G, Ozmore, Jillian R, Juliette, Kali, Torti, Erin, Normand, Elizabeth A, Granger, Leslie, Petersen, Andrea K, Au, Margaret G, Matheny, Juliann P, Phornphutkul, Chanika, Chambers, Mary-Kathryn, Fernández-Ramos, Joaquín-Alejandro, López-Laso, Eduardo, Kruer, Michael C, Bakhtiari, Somayeh, Zollino, Marcella, Morleo, Manuela, Marangi, Giuseppe, Mei, Davide, Pisano, Tiziana, Guerrini, Renzo, Louie, Raymond J, Childers, Anna, Everman, David B, Isidor, Betrand, Audebert-Bellanger, Séverine, Odent, Sylvie, Bonneau, Dominique, Gilbert-Dussardier, Brigitte, Redon, Richard, Bézieau, Stéphane, Laumonnier, Frédéric, Stoeckli, Esther T, Toutain, Annick, and Vuillaume, Marie-Laure
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, Epilepsy, Dendritic Spines, [SDV]Life Sciences [q-bio], Intellectual disability, Chick Embryo, Semaphorins, [SDV.GEN] Life Sciences [q-bio]/Genetics, General Medicine, Settore MED/03 - GENETICA MEDICA, Axon Guidance, [SDV] Life Sciences [q-bio], HEK293 Cells, SEMA6B, Intellectual Disability, Genetics, Animals, Humans, Original Article, Molecular Biology, Genetics (clinical)
Abstract: Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.
Published: 2022
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27. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

Author: Trudie Cottrell, Jacques C. Giltay, Richard H. van Jaarsveld, Elles M. J. Boon, Roger E. Stevenson, Michael A. Levy, Kimberly F. Doheny, Bekim Sadikovic, G. Bradley Schaefer, Roberto Bonasio, Muhammad Ansar, Vinodh Narayanan, Mieke M. van Haelst, Jill A. Fahrner, Marleen Simon, David B. Beck, Claudia A. L. Ruivenkamp, Sivagamy Sithambaram, Teresa Romeo Luperchio, Leandros Boukas, Marie-Christine Nougues, Hannah W. Moore, Marielle Alders, Renske Oegema, M. Mahdi Motazacker, Kay Metcalfe, Cyril Mignot, Jennifer Kerkhof, Gijs W. E. Santen, Jessica Bos, Sofia Douzgou, Siddharth Banka, Keri Ramsey, Boris Keren, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ANS - Complex Trait Genetics, AR&D - Amsterdam Reproduction & Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: Genetics, Epigenomics, DNA methylation, Neurodevelopmental disorders, Diagnostic markers, QH426-470, Biology, medicine.disease, Phenotype, Genome, Article, Neurodevelopmental disorder, DNA demethylation, CpG site, medicine, DNMT1, Medicine, Epigenetics, Author Correction, Molecular Biology, Genetics (clinical)
Abstract: TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.
Published: 2021
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28. Author Correction: Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

Author: Renske Oegema, Vinodh Narayanan, Marleen Simon, Trudie Cottrell, Marie-Christine Nougues, Mieke M. van Haelst, Gijs W. E. Santen, Roger E. Stevenson, Keri Ramsey, Kay Metcalfe, Jacques C. Giltay, Sivagamy Sithambaram, Teresa Romeo Luperchio, Leandros Boukas, Marielle Alders, Hannah W. Moore, Claudia A. L. Ruivenkamp, Jessica Bos, Richard H. van Jaarsveld, Jill A. Fahrner, David B. Beck, Sofia Douzgou, Jennifer Kerkhof, Muhammad Ansar, Michael A. Levy, G. Bradley Schaefer, Siddharth Banka, Roberto Bonasio, Kimberly F. Doheny, M. Mahdi Motazacker, Cyril Mignot, Elles M. J. Boon, Boris Keren, and Bekim Sadikovic
Subjects: Genetics, Medicine, Dna hypermethylation, QH426-470, Biology, Molecular Biology, Genome, Genetics (clinical), Whole blood
Published: 2021
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29. Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases

Author: Narayanan Veeraraghavan, Pankaj B. Agrawal, Paul Billings, Keri Ramsey, Casie A. Genetti, Martin G. Reese, Jeanette McCarthy, Terence C. Wong, Marcus Naymik, Catherine A. Brownstein, Vinodh Narayanan, Barry Moore, Britt Sabina Löscher, Mark Yandell, Francisco M. De La Vega, Edgar Javier Hernandez, Kiely N. James, Matthew J. Huentelman, Braden E. Boone, Shawn Levy, Stephen F. Kingsmore, Lucia Guidugli, Andre Franke, Erwin Frise, Shimul Chowdhury, Sander Pajusalu, Alan H. Beggs, and Katrin Õunap
Subjects: Male, Candidate gene, Genotype, Context (language use), Disease, QH426-470, Biology, Clinical decision support system, Genome, Rare Diseases, Artificial Intelligence, Databases, Genetic, Exome Sequencing, Genetics, Humans, Medical diagnosis, Molecular Biology, Exome sequencing, Genetics (clinical), Retrospective Studies, Whole genome sequencing, business.industry, Research, Retrospective cohort study, Genomics, Human genetics, Phenotype, Medicine, Molecular Medicine, Female, Artificial intelligence, business
Abstract: Background Clinical interpretation of genetic variants in the context of the patient’s phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease. Here we assess the diagnostic performance of Fabric GEM, a new, AI-based, clinical decision support tool for expediting genome interpretation. Methods We benchmarked GEM in a retrospective cohort of 119 probands, mostly NICU infants, diagnosed with rare genetic diseases, who received whole-genome or whole-exome sequencing (WGS, WES). We replicated our analyses in a separate cohort of 60 cases collected from five academic medical centers. For comparison, we also analyzed these cases with current state-of-the-art variant prioritization tools. Included in the comparisons were trio, duo, and singleton cases. Variants underpinning diagnoses spanned diverse modes of inheritance and types, including structural variants (SVs). Patient phenotypes were extracted from clinical notes by two means: manually and using an automated clinical natural language processing (CNLP) tool. Finally, 14 previously unsolved cases were reanalyzed. Results GEM ranked over 90% of the causal genes among the top or second candidate and prioritized for review a median of 3 candidate genes per case, using either manually curated or CNLP-derived phenotype descriptions. Ranking of trios and duos was unchanged when analyzed as singletons. In 17 of 20 cases with diagnostic SVs, GEM identified the causal SVs as the top candidate and in 19/20 within the top five, irrespective of whether SV calls were provided or inferred ab initio by GEM using its own internal SV detection algorithm. GEM showed similar performance in absence of parental genotypes. Analysis of 14 previously unsolved cases resulted in a novel finding for one case, candidates ultimately not advanced upon manual review for 3 cases, and no new findings for 10 cases. Conclusions GEM enabled diagnostic interpretation inclusive of all variant types through automated nomination of a very short list of candidate genes and disorders for final review and reporting. In combination with deep phenotyping by CNLP, GEM enables substantial automation of genetic disease diagnosis, potentially decreasing cost and expediting case review.
Published: 2021
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30. Progressive bilateral nuclear cataracts associated with cerebellar-facial-dental syndrome: case report, literature review, and identification of a new genetic variant

Author: Christopher Balak, Newell Belnap, Matthew J. Huentelman, Brianna Pandey, James Plotnik, Keri Ramsey, and Vinodh Narayanan
Subjects: Pathology, medicine.medical_specialty, TATA-Binding Protein Associated Factors, genetic structures, business.industry, Developmental Disabilities, Genetic disorder, Genetic variants, medicine.disease, eye diseases, Cataract, stomatognathic diseases, Ophthalmology, Cataracts, Cerebellum, Pediatrics, Perinatology and Child Health, Mutation, medicine, Humans, Identification (biology), Dysmorphic facial features, business, Child, Cerebellar hypoplasia
Abstract: Cerebellar-facial-dental syndrome (CFDS) is a newly described autosomal recessive genetic disorder characterized by mutations in the BRF1 gene. CFDS is clinically associated with dysmorphic facial features and cerebellar hypoplasia. We report visually significant progressive bilateral nuclear cataracts in a child with CFDS and identify a new causative genetic variant.
Published: 2021

31. Complex genetic network underlying the convergent of Rett Syndrome like (RTT-L) phenotype in neurodevelopmental disorders

Author: J. Dodson, Ignazio S. Piras, D. W. Craig, Newell Belnap, G. Mills, Ana M. Claasen, Marcus Naymik, Lorida Llaci, Vinodh Narayanan, B. Gerald, Meredith Sanchez-Castillo, P. Venugopal, Chris Balak, Szabolcs Szelinger, Ryan Richholt, Sampath Rangasamy, Raj Gupta, Isabelle Schrauwen, Ashley L. Siniard, M. Brzezinski, Keri Ramsey, Wayne M. Jepsen, M. D. De Both, R. Pillai, E. S. Frankel, M. J. Huentelman, and M. Sharifi
Subjects: Genetics, FOXG1, congenital, hereditary, and neonatal diseases and abnormalities, CDKL5, medicine, Rett syndrome, Atypical Rett syndrome, TCF4, Biology, medicine.disease, Phenotype, Exome sequencing, MECP2
Abstract: Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. Patients with features of classical Rett syndrome, but do not fulfill all the diagnostic criteria (e.g. absence of a MECP2 mutation), are defined as atypical Rett syndrome. Genes encoding for cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are more commonly found in patients with atypical Rett syndrome. Nevertheless, a subset of patients who are recognized to have an overlapping phenotype with RTT but are lacking a mutation in a gene that causes typical or atypical RTT are described as having Rett syndrome like phenotype (RTT-L). Whole Exome Sequencing (WES) of 8 RTT-L patients from our cohort revealed mutations in the genes GABRG2, GRIN1, ATP1A2, KCNQ2, KCNB1, TCF4, SEMA6B, and GRIN2A, which are seemingly unrelated to Rett syndrome genes. We hypothesized that the phenotypic overlap in RTT and RTT-L is caused by mutations in genes that affect common cellular pathways critical for normal brain development and function. We annotated the list of genes identified causing RTT-L from peer-reviewed articles and performed a protein-protein interaction (PPI) network analysis. We also investigated their interaction with RTT (typical or atypical) genes such as MECP2, CDKL5, NTNG1, and FOXG1. We found that the RTT-L-causing genes were enriched in the biological pathways such as circadian entrainment, the CREB pathway, and RET signaling, and neuronal processes like ion transport, synaptic transmission, and transcription. We conclude that genes that significantly interact with the PPI network established by RTT genes cause RTT-L, explaining the considerable feature overlap between genes that are indicated for RTT-L and RTT.
Published: 2020
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32. Front Cover, Volume 41, Issue 2

Author: Carmel G. McCullough, Szabolcs Szelinger, Newell Belnap, Keri Ramsey, Isabelle Schrauwen, Ana M. Claasen, Leah W. Burke, Ashley L. Siniard, Matthew J. Huentelman, Vinodh Narayanan, and David W. Craig
Subjects: Genetics, Genetics (clinical)
Published: 2020
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33. Modeling of Pontocerebellar Hypoplasia Type 1B and Chemical Mimicry in Patient-Derived Neural Stem Cells

Author: Ritin Sharma, Jacob M. Carlson, Vinodh Narayanan, Patrick Pirrotte, Kristin Leskoke, Judith A. Tello, Seema Plaisier, Melissa N. Martinez, Matthew J. Huentelman, Liberty François-Moutal, Francesca Vitali, Keri Ramsey, Ben Stansfield, Sampath Rangasamy, May Khanna, Patrick Pirotte, Llorida Llaci, Roberta Diaz Brinton, Jared M. Churko, and Krystine Garcia-Mansfield
Subjects: Mutation, biology, Exosome complex, Pontocerebellar hypoplasia, biology.organism_classification, medicine.disease, Proteomics, medicine.disease_cause, Small molecule, Neural stem cell, Cell biology, medicine, Chemical mimicry, Zebrafish
Abstract: Pontocerebellar Hypoplasia 1B (PCH1B) patients exhibit profound underdevelopment of the neocerebellum and its adjacent structures, leading to severe developmental delays as well as poor survival. Here, we report a new case of PCH1B with a known mutation in EXOSC3, a component of the RNA exosome. We reprogrammed blood from the PCH1B patient and the healthy carrier parents into human induced pluripotent stem cells and differentiated these cells into neural stem cells (NSCs). Proteomic content was analyzed by mass spectrometry to reveal a slight underexpression of mutated EXOSC3 in the PCH1B patient. We discovered that several processes implicated in cell differentiation were impaired. NSCs from the mother were incubated with ERD03, a small molecule rationally developed to model PCH1B in zebrafish and analyzed by high-throughput mass spectrometry-based proteomics. In addition to affecting individual protein expression, we demonstrated the ability of the compound ERD03 to mimic PCH1B-induced protein pathways.
Published: 2020
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34. Primrose syndrome: Characterization of the phenotype in42 patients

Author: Erica H. Gerkes, Pietro Strisciuglio, Renata Lazari Sandoval, Todd Waters, A. Rossi, Renata Posmyk, Sheela Unger, Constance T. R. M. Stumpel, Hanne B Hove, Tina Barbaro-Dieber, Marco Tartaglia, Keri Ramsey, Petr E. Jira, Daniel R. Carvalho, Vinodh Narayanan, Leonie A. Menke, Katherine Lachlan, Michael J. Gambello, Viviana Cordeddu, Sandra Jansen, Marrit M. Hitzert, Peter D. Turnpenny, Blanca Gener, Daniela Melis, Raoul C.M. Hennekam, Damara Ortiz, Clare Turnbull, Kyra E. Stuurman, Eline Overwater, Alberto J. Espay, Pediatric surgery, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, General Paediatrics, ANS - Cellular & Molecular Mechanisms, ARD - Amsterdam Reproduction and Development, Human Genetics, Graduate School, ACS - Heart failure & arrhythmias, APH - Quality of Care, Melis, D., Carvalho, D., Barbaro-Dieber, T., Espay, A. J., Gambello, M. J., Gener, B., Gerkes, E., Hitzert, M. M., Hove, H. B., Jansen, S., Jira, P. E., Lachlan, K., Menke, L. A., Narayanan, V., Ortiz, D., Overwater, E., Posmyk, R., Ramsey, K., Rossi, A., Sandoval, R. L., Stumpel, C., Stuurman, K. E., Cordeddu, V., Turnpenny, P., Strisciuglio, P., Tartaglia, M., Unger, S., Waters, T., Turnbull, C., and Hennekam, R. C.
Subjects: 0301 basic medicine, Male, Pathology, alpha‐fetoprotein, Transcription Factor, 030105 genetics & heredity, Carbon-Carbon Double Bond Isomerase, Racemases and Epimerase, Intellectual disability, ectopic calcifications, Primrose syndrome, Child, Wasting, Enoyl-CoA Hydratase, Genetics (clinical), ABNORMALITIES, 3-Hydroxyacyl CoA Dehydrogenases, Calcinosis, ZBTB20, Middle Aged, Ear Disease, Acetyl-CoA C-Acyltransferase, CANCER, Mitochondria, Muscular Atrophy, DIFFERENTIATION, Phenotype, Child, Preschool, Calcinosi, Original Article, Female, medicine.symptom, Human, Adult, medicine.medical_specialty, Heterozygote, Adolescent, alpha-fetoprotein, overgrowth, Mutation, Missense, Racemases and Epimerases, Nerve Tissue Proteins, Genetic Association Studie, 03 medical and health sciences, Frontal Bossing, Young Adult, Testicular Neoplasms, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Testicular Neoplasm, Ear Diseases, Genetic Association Studies, Muscle contracture, MUTATIONS, business.industry, ectopic calcification, 3-Hydroxyacyl CoA Dehydrogenase, Macrocephaly, Infant, Original Articles, medicine.disease, Carbon-Carbon Double Bond Isomerases, Megalencephaly, ALPHA, 030104 developmental biology, Palpebral fissure, Face, Nerve Tissue Protein, Mutation, business, FINGER PROTEIN ZBTB20, Calcification, Transcription Factors
Abstract: Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down‐slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha‐fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype‐phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
Published: 2020
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35. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

Author: Brett V. Johnson, Raman Kumar, Sabrina Oishi, Suzy Alexander, Maria Kasherman, Michelle Sanchez Vega, Atma Ivancevic, Alison Gardner, Deepti Domingo, Mark Corbett, Euan Parnell, Sehyoun Yoon, Tracey Oh, Matthew Lines, Henrietta Lefroy, Usha Kini, Margot Van Allen, Sabine Grønborg, Sandra Mercier, Sébastien Küry, Stéphane Bézieau, Laurent Pasquier, Martine Raynaud, Alexandra Afenjar, Thierry Billette de Villemeur, Boris Keren, Julie Désir, Lionel Van Maldergem, Martina Marangoni, Nicola Dikow, David A. Koolen, Peter M. VanHasselt, Marjan Weiss, Petra Zwijnenburg, Joaquim Sa, Claudia Falcao Reis, Carlos López-Otín, Olaya Santiago-Fernández, Alberto Fernández-Jaén, Anita Rauch, Katharina Steindl, Pascal Joset, Amy Goldstein, Suneeta Madan-Khetarpal, Elena Infante, Elaine Zackai, Carey Mcdougall, Vinodh Narayanan, Keri Ramsey, Saadet Mercimek-Andrews, Loren Pena, Vandana Shashi, Kelly Schoch, Jennifer A. Sullivan, Filippo Pinto e Vairo, Pavel N. Pichurin, Sarah A. Ewing, Sarah S. Barnett, Eric W. Klee, M. Scott Perry, Mary Kay Koenig, Catherine E. Keegan, Jane L. Schuette, Stephanie Asher, Yezmin Perilla-Young, Laurie D. Smith, Jill A. Rosenfeld, Elizabeth Bhoj, Paige Kaplan, Dong Li, Renske Oegema, Ellen van Binsbergen, Bert van der Zwaag, Marie Falkenberg Smeland, Ioana Cutcutache, Matthew Page, Martin Armstrong, Angela E. Lin, Marcie A. Steeves, Nicolette den Hollander, Mariëtte J.V. Hoffer, Margot R.F. Reijnders, Serwet Demirdas, Daniel C. Koboldt, Dennis Bartholomew, Theresa Mihalic Mosher, Scott E. Hickey, Christine Shieh, Pedro A. Sanchez-Lara, John M. Graham, Kamer Tezcan, G.B. Schaefer, Noelle R. Danylchuk, Alexander Asamoah, Kelly E. Jackson, Naomi Yachelevich, Margaret Au, Luis A. Pérez-Jurado, Tjitske Kleefstra, Peter Penzes, Stephen A. Wood, Thomas Burne, Tyler Mark Pierson, Michael Piper, Jozef Gécz, Lachlan A. Jolly, Maria T. Acosta, David R. Adams, Aaron Aday, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Deborah Barbouth, Gabriel F. Batzli, Alan H. Beggs, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jean M. Davidson, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Annika M. Dries, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Gregory M. Enns, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Noah D. Friedman, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Jason D. Merker, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Genecee Renteri, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, David A. Sweetser, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Tiphanie P. Vogel, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Stephan Zuchner, William Gahl, Clinical Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), ACS - Atherosclerosis & ischemic syndromes, MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
Subjects: Male, 0301 basic medicine, Brain malformation, Developmental Disabilities, INTERACTS, USP9X, Haploinsufficiency, in-vitro, CELL-MIGRATION, Deubiquitylating enzyme, Biology, Hippocampus, of-function mutations, Article, liquid facets, TGFβ, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, TGF beta, Transforming Growth Factor beta, Intellectual Disability, Intellectual disability, medicine, Animals, Humans, Missense mutation, deubiquitinating enzyme, Biological Psychiatry, fam/usp9x, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Male Phenotype, medicine.disease, Phenotype, Hypotonia, 030104 developmental biology, Female, medicine.symptom, Ubiquitin Thiolesterase, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Transforming growth factor
Abstract: Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access) BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.
Published: 2020
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36. Damaging de novo missense variants in EEF1A2lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

Author: Laurine Perrin, Sha Tang, Brandon S. Guida, Tjitske Kleefstra, Marjolein H. Willemsen, Heather Stickney, Michael C. Kruer, Keri Ramsey, Heather C Mefford, Lynette G. Sadleir, Bobby P. C. Koeleman, Evelyn Sattlegger, Angela E. Lin, Sara A. Lewis, Marcello Scala, Sergio Padilla-Lopez, Luis O. Rohena, Joaquim Sa, Marie Laure Mathieu, Floor E. Jansen, Joy Y. Sebe, David W. Raible, Giorgio Casari, Gemma L. Carvill, Ingrid E. Scheffer, Paul A. Caruso, Robert Huether, Mariasavina Severino, Candace T. Myers, Eva H. Brilstra, Ashwin A. Bhandiwad, Katherine L. Helbig, Somayeh Bakhtiari, Sehribani Ulusoy Oktay, Gaetan Lesca, Vinodh Narayanan, Georgina Hollingsworth, Tyler N. Kruer, Christel Depienne, Valeria Capra, Pasquale Striano, Timothy Feyma, Deepak Gill, Andrea Accogli, Caroline Nava, Carvill, G. L., Helbig, K. L., Myers, C. T., Scala, M., Huether, R., Lewis, S., Kruer, T. N., Guida, B. S., Bakhtiari, S., Sebe, J., Tang, S., Stickney, H., Oktay, S. U., Bhandiwad, A. A., Ramsey, K., Narayanan, V., Feyma, T., Rohena, L. O., Accogli, A., Severino, M., Hollingsworth, G., Gill, D., Depienne, C., Nava, C., Sadleir, L. G., Caruso, P. A., Lin, A. E., Jansen, F. E., Koeleman, B., Brilstra, E., Willemsen, M. H., Kleefstra, T., Sa, J., Mathieu, M. -L., Perrin, L., Lesca, G., Striano, P., Casari, G., Scheffer, I. E., Raible, D., Sattlegger, E., Capra, V., Padilla-Lopez, S., Mefford, H. C., and Kruer, M. C.
Subjects: Adult, Male, de novo, Heterozygote, Adolescent, Encephalopathy, Choreoathetosis, Mutation, Missense, EEF1A2, Haploinsufficiency, Biology, Article, 03 medical and health sciences, Epilepsy, All institutes and research themes of the Radboud University Medical Center, Peptide Elongation Factor 1, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), 030304 developmental biology, Dystonia, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 030305 genetics & heredity, Genetic Complementation Test, medicine.disease, yeast complementation assay, Protein Structure, Tertiary, dyskinesia, Child, Preschool, epilepsy, Cerebellar atrophy, Epilepsy, Generalized, Female, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.
Published: 2020

37. eP329: Genome sequencing uncovers molecular cause in a case with epileptic encephalopathy

Author: Anjana Chandrasekhar, Zinayida Schlachetzki, Alison Coffey, Ali Fenstermaker, Richard Wang, Krista Bluske, Marcus Naymik, Sampath Rangasamy, Anna Bonfitto, Wayne Jepsen, Matt Huentelman, Vinodh Narayanan, Keri Ramsey, Akanchha Kesari, Denise Perry, and Ryan Taft
Subjects: Genetics (clinical)
Published: 2022
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38. De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy

Author: Chris Balak, Dan W. Nowakowski, Ali Fatemi, Sampath Rangasamy, Catherine A. Brownstein, Pankaj B. Agrawal, Vinodh Narayanan, Keri Ramsey, Ellen Grant, Kyoko Okada, Hsin-Yi Henry Ho, Julie S. Cohen, Sanjay P. Prabhu, Jiahai Shi, Klaus Schmitz-Abe, and Monica H. Wojcik
Subjects: Models, Molecular, 0301 basic medicine, Proband, Nervous system, Microcephaly, Protein Conformation, Gene Expression, Kinesins, Spinal Muscular Atrophies of Childhood, kinesin, Whole Exome Sequencing, Mice, Models, 2.1 Biological and endogenous factors, Missense mutation, microcephaly, Aetiology, Genetics (clinical), Exome sequencing, Pediatric, Arthrogryposis, Genetics, Brain, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurological, Olivopontocerebellar Atrophies, Kinesin, medicine.symptom, Clinical Sciences, Pontocerebellar hypoplasia, Biology, Article, arthrogryposis, 03 medical and health sciences, Rare Diseases, Clinical Research, Exome Sequencing, Cell Adhesion, medicine, Animals, Humans, Amino Acid Sequence, Animal, pontocerebellar hypoplasia, KIF26B, Neurosciences, Molecular, medicine.disease, Brain Disorders, Disease Models, Animal, 030104 developmental biology, Disease Models
Abstract: KIF26B is a member of the kinesin superfamily with evolutionarily conserved functions in controlling aspects of embryogenesis, including the development of the nervous system, though its function is incompletely understood. We describe an infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. We performed whole exome sequencing on the trio and identified a de novo KIF26B missense variant, p.Gly546Ser, in the proband. This variant alters a highly conserved amino acid residue that is part of the phosphate-binding loop motif and motor-like domain and is deemed pathogenic by several in silico methods. Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Overall, KIF26B may play a critical role in the brain development and, when mutated, cause pontocerebellar hypoplasia with arthrogryposis.
Published: 2018
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39. Two additional males with X‐linked, syndromic mental retardation carry de novo mutations in HNRNPH2

Author: Chris Balak, Szabolcs Szelinger, Marcus Naymik, Vinodh Narayanan, Meredith Sanchez-Castillo, Ignazio S. Piras, Lorida Llaci, Matthew J. Huentelman, Sampathkumar Rangasamy, Cherae Bilagody, Newell Belnap, Matthew De Both, Keri Ramsey, Wayne M. Jepsen, Raj Gupta, and Richa Pandey
Subjects: Genetics, business.industry, Mutation (genetic algorithm), Intellectual disability, MEDLINE, Medicine, business, medicine.disease, Genetics (clinical), De novo mutations
Published: 2019
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40. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author: Naomi Meeks, Stefan Kindler, Anya Revah-Politi, Alexander P.A. Stegmann, Vinodh Narayanan, Dominique Bonneau, Claudia Schob, Jill A. Rosenfeld, Jennifer E. Posey, Tim M. Strom, LaDonna Immken, Tjitske Kleefstra, Jolanda H. Schieving, Katherine L. Helbig, Estelle Colin, Magalie Barth, Tamar Harel, Matthew J. Huentelman, James R. Lupski, Benjamin Cogné, Han G. Brunner, Yaping Yang, Sébastien Küry, Jenny Morton, Erica H. Gerkes, Keri Ramsey, Marine Tessarech, Zeynep Coban-Akdemir, Shimon Edvardson, Hans-Jürgen Kreienkamp, Nelly Oundjian, Davor Lessel, Christian Kubisch, Thomas Besnard, Jonas Denecke, Orly Elpeleg, Ana M. Claasen, Kelsey Zegar, Mohammad K. Eldomery, Sandra Mercier, Margot R.F. Reijnders, Stéphane Bézieau, Univ Angers, Okina, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Central Nervous System, Male, DISRUPTION, INTELLECTUAL DISABILITY, Developmental Disabilities, PROTEIN, DISEASE, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, Global developmental delay, Amino Acids, Child, Genetics (clinical), Genetics, Adenosine Triphosphatases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Translation (biology), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, FAMILY, Child, Preschool, Female, RNA Helicases, MODULE, Adolescent, Mutation, Missense, RNA GRANULES, Biology, Article, Cell Line, 03 medical and health sciences, Stress granule, Cell Line, Tumor, medicine, Humans, HELICASE, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], STRESS GRANULES, Helicase, RNA, Correction, medicine.disease, GENE, 030104 developmental biology, HEK293 Cells, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Contains fulltext : 182457.pdf (Publisher’s version ) (Open Access) DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.
Published: 2017
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41. Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

Author: Jinhong Wie, Apoorva Bharthur, Morgan Wolfgang, Qi Zhang, Keri Ramsey, Kimberly Aranda, Dejian Ren, Vinodh Narayanan, and Yandong Zhou
Subjects: 0301 basic medicine, Male, Physiology, DNA Mutational Analysis, General Physics and Astronomy, Datasets as Topic, medicine.disease_cause, Hippocampus, Severity of Illness Index, Ion channels in the nervous system, Ion Channels, Mice, 0302 clinical medicine, Intellectual disability, Gene Knock-In Techniques, lcsh:Science, Child, Membrane potential, Mice, Knockout, Mutation, Multidisciplinary, Phenotype, Knockout mouse, Protein subunit, Science, Primary Cell Culture, Nerve Tissue Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Protein Domains, Intellectual Disability, Exome Sequencing, medicine, Animals, Humans, HEK 293 cells, Membrane Proteins, General Chemistry, Dendrites, medicine.disease, Disease Models, Animal, 030104 developmental biology, HEK293 Cells, lcsh:Q, Carrier Proteins, Neuroscience, 030217 neurology & neurosurgery, Function (biology)
Abstract: The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. The auxiliary subunits of the channel and their functions in mammals are largely unknown. In this study, we demonstrate that two large proteins UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization. UNC80 lacking this domain, as found in human patients, still supports whole-cell NALCN currents but lacks dendritic localization. Our results establish the subunit composition of the NALCN complex, uncover the inter-subunit interaction domains, reveal the functional significance of regulation of dendritic membrane potential by the sodium-leak channel complex, and provide evidence supporting that genetic variations found in individuals with intellectual disability are the causes for the phenotype observed in patients., The sodium-leak channel NALCN controls the resting membrane potentials of neurons. Here, the authors identified two subunits of NALCN, UNC80 and UNC79. Domains in UNC80, which are mutated in individuals with intellectual disability, interact to achieve the dendritic localization of NALCN complex.
Published: 2019

42. Clinical and genetic characterization of individuals with predicted deleterious PHIP variants

Author: Ashley Wilson, Jane Juusola, Keri Ramsey, Antonio Vitobello, Wendy K. Chung, Marie-Noelle Bonnet Dupeyron, Kirsten E. Craddock, Volkan Okur, Jennifer Heeley, Laurence Faivre, and Erica H. Gerkes
Subjects: Genetics, 0303 health sciences, Mutation, IDENTIFICATION, business.industry, media_common.quotation_subject, Nonsense, General Medicine, medicine.disease, medicine.disease_cause, Hypotonia, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, Missense mutation, Medicine, Attention deficit hyperactivity disorder, Autism, medicine.symptom, business, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract: Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellectual disability/developmental delay, obesity/overweight, and dysmorphic features (BIDOD syndrome). We report an additional 10 individuals with pleckstrin homology domain-interacting protein (PHIP)-predicted deleterious variants (four frameshift, three missense, two nonsense, and one splice site; six of which are confirmed de novo). The mutation spectrum is diverse, and there is no clustering of mutations across the protein. The clinical phenotype of these individuals is consistent with previous reports and includes behavioral problems, intellectual disability, developmental delay, hypotonia, and dysmorphic features. The additional individuals we report have a lower frequency of obesity than previous reports and a higher frequency of gastrointestinal problems, social deficits, and behavioral challenges. Characterizing additional individuals with diverse mutations longitudinally will provide better natural history data to assist with medical management and educational and behavioral support.
Published: 2019
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43. Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD)

Author: Matt De Both, Ana M. Claasen, Lorida Llaci, Ryan Richholt, Marcus Naymik, Vinodh Narayanan, Chris Balak, Ashley L. Siniard, Tyler Izat, Ignazio S. Piras, Matthew J. Huentelman, Keri Ramsey, David Craig, Isabelle Schrauwen, Wayne M. Jepsen, Sampathkumar Rangasamy, Szabolcs Szelinger, and Newell Belnap
Subjects: Male, Pathology, medicine.medical_specialty, Heterozygote, Ataxia, Biology, Compound heterozygosity, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, Humans, Qc-SNARE Proteins, Keratoderma, Child, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, Ichthyosis, 030305 genetics & heredity, Leukodystrophy, Qb-SNARE Proteins, medicine.disease, Prognosis, Hypotonia, Hereditary Central Nervous System Demyelinating Diseases, Speech delay, Mutation, medicine.symptom
Abstract: Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (p.Leu119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient’s blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.
Published: 2019

44. Congenital myasthenic syndrome caused by a frameshift insertion mutation in

Author: Szabolcs, Szelinger, Jonida, Krate, Keri, Ramsey, Samuel P, Strom, Perry B, Shieh, Hane, Lee, Newell, Belnap, Chris, Balak, Ashley L, Siniard, Megan, Russell, Ryan, Richholt, Matt De, Both, Ana M, Claasen, Isabelle, Schrauwen, Stanley F, Nelson, Matthew J, Huentelman, David W, Craig, Samuel P, Yang, Steven A, Moore, Kumaraswamy, Sivakumar, Vinodh, Narayanan, and Sampathkumar, Rangasamy
Subjects: Article
Abstract: Objective Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families. Methods Muscle biopsies, EMG, and whole-exome sequencing were performed. Results All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology. Conclusions These results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.
Published: 2019

45. Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice

Author: Milka, Pringsheim, Diana, Mitter, Simone, Schröder, Rita, Warthemann, Kim, Plümacher, Gerhard, Kluger, Martina, Baethmann, Thomas, Bast, Sarah, Braun, Hans-Martin, Büttel, Elizabeth, Conover, Carolina, Courage, Alexandre N, Datta, Angelika, Eger, Theresa A, Grebe, Annette, Hasse-Wittmer, Marion, Heruth, Karen, Höft, Angela M, Kaindl, Stephanie, Karch, Torsten, Kautzky, Georg C, Korenke, Bernd, Kruse, Richard E, Lutz, Heymut, Omran, Steffi, Patzer, Heike, Philippi, Keri, Ramsey, Tina, Rating, Angelika, Rieß, Mareike, Schimmel, Rachel, Westman, Frank-Martin, Zech, Birgit, Zirn, Pauline A, Ulmke, Godwin, Sokpor, Tran, Tuoc, Andreas, Leha, Martin, Staudt, Knut, Brockmann, HUSLAB, Medicum, Department of Medical and Clinical Genetics, and University of Helsinki
Subjects: EXPRESSION, DISORDER, Genotype, MIGRATION, Mice, Transgenic, Nerve Tissue Proteins, 3124 Neurology and psychiatry, Intellectual Disability, Rett Syndrome, Animals, Humans, Research Articles, TELENCEPHALON, MUTATIONS, 3112 Neurosciences, Brain, Forkhead Transcription Factors, ASSOCIATION, CORPUS-CALLOSUM, Phenotype, nervous system, Child Development Disorders, Pervasive, OLIGODENDROCYTE, Microcephaly, FORNIX, Female, CONGENITAL VARIANT, Research Article
Abstract: Objective FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. Methods We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. Results Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. Interpretation Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.
Published: 2019

46. Clinical and genetic characterization of individuals with predicted deleterious

Author: Kirsten E, Craddock, Volkan, Okur, Ashley, Wilson, Erica H, Gerkes, Keri, Ramsey, Jennifer M, Heeley, Jane, Juusola, Antonio, Vitobello, Marie-Noelle Bonnet, Dupeyron, Laurence, Faivre, and Wendy K, Chung
Subjects: Male, Heterozygote, almond-shaped palpebral fissure, Adolescent, Developmental Disabilities, gastroesophageal reflux, autism, chronic constipation, generalized neonatal hypotonia, abdominal obesity, Intellectual Disability, blurred vision, Exome Sequencing, mild global developmental delay, Humans, mild, thickened helices, Abnormalities, Multiple, Exome, Child, Frameshift Mutation, aggressive behavior, amblyopia, anteverted nares, clinodactyly of the 5th finger, high forehead, Imidazoles, Intracellular Signaling Peptides and Proteins, Infant, Phenotype, attention deficit hyperactivity disorder, Follow-up Report, Child, Preschool, Mutation, synophrys, Muscle Hypotonia, Female, chronic fatigue, Transcription Factors, 2-3 toe cutaneous syndactyly, thin upper lip vermilion
Abstract: Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellectual disability/developmental delay, obesity/overweight, and dysmorphic features (BIDOD syndrome). We report an additional 10 individuals with pleckstrin homology domain-interacting protein (PHIP)-predicted deleterious variants (four frameshift, three missense, two nonsense, and one splice site; six of which are confirmed de novo). The mutation spectrum is diverse, and there is no clustering of mutations across the protein. The clinical phenotype of these individuals is consistent with previous reports and includes behavioral problems, intellectual disability, developmental delay, hypotonia, and dysmorphic features. The additional individuals we report have a lower frequency of obesity than previous reports and a higher frequency of gastrointestinal problems, social deficits, and behavioral challenges. Characterizing additional individuals with diverse mutations longitudinally will provide better natural history data to assist with medical management and educational and behavioral support.
Published: 2019

47. Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

Author: Chris Balak, Hélène Dollfus, Sumaiya Iqbal, Newell Belnap, Kristin G. Monaghan, Lorida Llaci, Sampathkumar Rangasamy, Véronique Geoffroy, Jean-Louis Mandel, Dennis Lal, Jamel Chelly, Keri Ramsey, Maïté Courel, Kirsty McWalter, Ignazio S. Piras, Marcus Naymik, Rolph Pfundt, Michèle Ernoult-Lange, Wayne M. Jepsen, Vinodh Narayanan, Antony Le Béchec, Dominique Weil, Kristine K. Bachman, Ryan Richholt, Szabolcs Szelinger, Matthew J. Huentelman, Johanna ter Beest, Arthur Campbell, Ingrid M. Wentzensen, Francesca Mattioli, Marianne Bénard, Jean Muller, Jean-François Deleuze, Amélie Piton, Anne Boland, Elise Schaefer, Patrick Rump, Matt De Both, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], GeneDx [Gaithersburg, MD, USA], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Les Hôpitaux Universitaires de Strasbourg (HUS), Cologne Center for Genomics, University of Cologne, Laboratoire de Biologie du Développement [IBPS] (LBD), weil, dominique, The Translational Genomics Research Institute (TGen), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), University of Groningen [Groningen], Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CEA- Saclay (CEA), Lerner Research Institute [Cleveland, OH, USA], Cleveland Clinic, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CDF (laboratoire)), Collège de France (CdF (institution)), and Bénard, Marianne
Subjects: [SDV]Life Sciences [q-bio], RecA domain, DENDRITES, DEAD-box RNA Helicases, 0302 clinical medicine, Missense mutation, NEURONS, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, DEAD-box, RNA Helicase A, [SDV] Life Sciences [q-bio], helicase, intellectual disability, missense variants, DDX3X, COMMON-CAUSE, mRNA metabolism, RNA helicase, processing bodies, DEAD box, PROTEINS, Mutation, Missense, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, METABOLISM, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Proto-Oncogene Proteins, DDX6, TRANSLATIONAL REPRESSION, REVEALS, Humans, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Messenger RNA, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, MUTATIONS, Helicase, RNA, DExD/H-box, FRAMEWORK, neurodevelopmental disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, p-bodies, biology.protein, 030217 neurology & neurosurgery
Abstract: International audience; The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
Published: 2019
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48. Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1

Author: Jonida Krate, Samuel P. Strom, Ryan Richholt, Vinodh Narayanan, Matt De Both, Kumaraswamy Sivakumar, Newell Belnap, Sampathkumar Rangasamy, Ashley L. Siniard, Perry B. Shieh, Megan Russell, David Craig, Ana M. Claasen, Isabelle Schrauwen, Hane Lee, Chris Balak, Samuel P. Yang, Stanley F. Nelson, Matthew J. Huentelman, Keri Ramsey, Steven A. Moore, and Szabolcs Szelinger
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, business.industry, Muscle weakness, 030105 genetics & heredity, Congenital myasthenic syndrome, medicine.disease, Uniparental disomy, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Postsynaptic potential, medicine, Neurology (clinical), Insertion, Repetitive nerve stimulation, medicine.symptom, business, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: ObjectiveDescription of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.MethodsMuscle biopsies, EMG, and whole-exome sequencing were performed.ResultsAll 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology.ConclusionsThese results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.
Published: 2020
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49. Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia

Author: Leah W. Burke, Vinodh Narayanan, Keri Ramsey, Carmel G McCullough, Szabolcs Szelinger, David Craig, Matthew J. Huentelman, Isabelle Schrauwen, Newell Belnap, Ana M. Claasen, and Ashley L. Siniard
Subjects: Gene isoform, Genotype, Adaptor Protein Complex 4, Biology, 03 medical and health sciences, symbols.namesake, Exon, Gene expression, Genetics, Humans, splice, Genetic Predisposition to Disease, Global developmental delay, Genetics (clinical), Exome sequencing, Alleles, Genetic Association Studies, 030304 developmental biology, Sanger sequencing, 0303 health sciences, Spastic Paraplegia, Hereditary, Siblings, 030305 genetics & heredity, Introns, Pedigree, Alternative Splicing, Phenotype, RNA splicing, symbols, Female
Abstract: We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome. In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms.
Published: 2018

50. A novel variant in TAF1 affects gene expression and is associated with X-linked TAF1 intellectual disability syndrome

Author: Samantha Perez-Miller, May Khanna, Szabolcs Szelinger, Rajesh Khanna, Karen A. Lewis, Sara S. Parker, Mark A. Nelson, Sydney A. Rice, Erika Liktor-Busa, David Craig, Laurel Johnstone, Vinodh Narayanan, Heather R. Dahlin, Edith H. Wang, Grant D Senner, Michael F. Hammer, Sarah Elizabeth Hurst, Keri Ramsey, and Aubin Moutal
Subjects: 0301 basic medicine, Genetics, Whole genome sequencing, Candidate gene, Biology, Genome, X-inactivation, Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, MRNA Sequencing, Global developmental delay, Gene, 030217 neurology & neurosurgery
Abstract: We investigated the genome of a 5-year-old male who presented with global developmental delay (motor, cognitive, and speech), hypotonia, possibly ataxia, and cerebellar hypoplasia of unknown origin. Whole genome sequencing (WGS) and mRNA sequencing (RNA-seq) were performed on a family having an affected proband, his unaffected parents, and maternal grandfather. To explore the molecular and functional consequences of the variant, we performed cell proliferation assays, quantitative real-time PCR (qRT-PCR) array, immunoblotting, calcium imaging, and neurite outgrowth experiments in SH-SY5Y neuroblastoma cells to compare the properties of the wild-type TATA-box-binding protein factor 1 (TAF1), deletion of TAF1, and TAF1 variant p.Ser1600Gly samples. The whole genome data identified several gene variants. However, the genome sequence data failed to implicate a candidate gene as many of the variants were of unknown significance. By combining genome sequence data with transcriptomic data, a probable candidate variant, p.Ser1600Gly, emerged in TAF1. Moreover, the RNA-seq data revealed a 90:10 extremely skewed X-chromosome inactivation (XCI) in the mother. Our results showed that neuronal ion channel genes were differentially expressed between TAF1 deletion and TAF1 variant p.Ser1600Gly cells, when compared with their respective controls, and that the TAF1 variant may impair neuronal differentiation and cell proliferation. Taken together, our data suggest that this novel variant in TAF1 plays a key role in the development of a recently described X-linked syndrome, TAF1 intellectual disability syndrome, and further extends our knowledge of a potential link between TAF1 deficiency and defects in neuronal cell function.
Published: 2018
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