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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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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. 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

21. 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

22. 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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23. 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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24. 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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25. 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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26. 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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27. 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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28. 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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29. 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

30. 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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31. The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants

Author

Anna Zachariou, Peter D Turnpenny, Linda M. Randolph, Carlos E. Prada, Angelo Selicorni, Nazneen Rahman, Christine Fauth, Ajith Kumar, Deborah J. Shears, Melissa Lees, Valérie Cormier-Daire, Shazia Mahamdallie, Mieke C. Bouma, Kathryn G. Miller, Katherine Neas, Vinod Varghese, Deciphering Developmental Disorders Study, Renata Posmyk, Chey Loveday, Lise Aksglaede, Ruth Newbury-Ecob, Keri Ramsey, Laura Yates, Daniela T. Pilz, David A. Koolen, I. Karen Temple, Beau Crabb, Cyril Mignot, Katrina Tatton-Brown, Daniela Q.C.M. Barge-Schaapveld, Blanca Gener, Cathy Kirally-Borri, Mohnish Suri, Agnete Jørgensen, David Goudie, Catherine Mercer, Carlo Marcelis, Anthony Renwick, Lionel Val Maldergem, Diana Baralle, Naomi Yachelevich, Matthew F. Hunter, Hermine E. Veenstra-Knol, Sarina G. Kant, Moira Blyth, Tessa Homfray, Jeroen Breckpot, Anatalia Labilloy, Tabib Dabir, and Richard Fisher

Subjects
0301 basic medicine, Joint hypermobility, Pediatrics, medicine.medical_specialty, viruses, Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, Clinical study, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, medicine, Kyphoscoliosis, overgrowth, Tatton-Brown-Rahman, business.industry, Articles, biochemical phenomena, metabolism, and nutrition, medicine.disease, Obesity, Hypotonia, 3. Good health, 030104 developmental biology, Current management, intellectual disability, 030220 oncology & carcinogenesis, DNMT3A, TATTON-BROWN-RAHMAN SYNDROME, medicine.symptom, business, Research Article
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 novoDNMT3A 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. ispartof: Wellcome Open Res vol:3 pages:46- ispartof: location:England status: Published online

Published
2018

32. CORRIGENDUM: The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations

Author

Chun-An Chen, Daniëlle G M Bosch, Megan T Cho ScM, Jill A Rosenfeld, Marwan Shinawi, Richard Alan Lewis, John Mann, Parul Jayakar, Katelyn Payne, Laurence Walsh, Timothy Moss, Allison Schreiber, Cheri Schoonveld, Kristin G Monaghan, Frances Elmslie, Ganka Douglas, F Nienke Boonstra, Francisca Millan, Frans P M Cremers, Dianalee McKnight, Gabriele Richard, Jane Juusola, Fran Kendall, Keri Ramsey, Kwame Anyane-Yeboa, Elfrida Malkin, Wendy K Chung, Dmitriy Niyazov, Juan M Pascual, Magdalena Walkiewicz, Vivekanand Veluchamy, Chumei Li, Fuki M Hisama, Bert B A de Vries, and Christian Schaaf

Subjects
Genetics (clinical)
Abstract

This corrects the article DOI: 10.1038/gim.2016.18.

Published
2017

33. Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

Author

Vinodh Narayanan, Magalie Barth, Majid Mojarrad, Christian de Goede, Penny Fallon, Reza Maroofian, Yanick J. Crow, Russell C. Dale, Valentina De Giorgis, Magnhild Rasmussen, Soe Mar, Mark P. Gorman, Atieh Eslahi, Gary McCullagh, Jean-Pierre S-M Lin, Simona Orcesi, Manju A. Kurian, Michael C Fahey, Isabelle Desguerre, Tommy Stödberg, Gillian I. Rice, Florence Petit, Cindy Colson, Amy Waldman, Marie Hully, Naoki Kitabayashi, Laura Martí-Sánchez, Begoña De Azua, Belén Pérez-Dueñas, Adeline Vanderver, Pilar Rodríguez-Pombo, Nicole Ulrick, François Rivier, Niklas Darin, Corinne De Laet, Annabel C.E. Burton, Alex J. Fay, Nirmala Rani Gowrinathan, Annick Toutain, Mehran Beiraghi Toosi, John H. Livingston, Agathe Roubertie, Keri Ramsey, Florence Uettwiller, Maria Luisa Carpanelli, Alfredo M. Cerisola, Tracy A Briggs, Nicolas Leboucq, Matthew A. Lines, Juan Darío Ortigoza-Escobar, Elisa Fazzi, Federica Rachele Danti, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Neuroradiologie[Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Division of Evolution and Genomic Science [Manchester], School of Biological Sciences [Manchester]-Faculty of Biology, Medicine and Health [Manchester], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Fondation 'Neurological Institute C. Mondino ', CHU de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Genetic Medicine, University of Manchester, Manchester Academic Heath Science Centre, European Research Council, Agence Nationale de la Recherche (France), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau

Subjects
0301 basic medicine, Male, Pathology, Aicardi–Goutières syndrome, Adenosine Deaminase, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Aicardi-Goutières syndrome, medicine.disease_cause, Compound heterozygosity, Pediatrics, Bilateral striatal necrosis, bilateral striatal necrosis, Interquartile range, Medicine, Missense mutation, Child, ComputingMilieux_MISCELLANEOUS, Mutation, spastic paraparesis, RNA-Binding Proteins, General Medicine, Perinatology and Child Health, Idiopathic basal ganglia calcification, 3. Good health, Dystonia, Phenotype, Spastic paraparesis, Child, Preschool, Interferon Type I, Biomarker (medicine), Female, dystonia, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Context (language use), Nervous System Malformations, Article, 03 medical and health sciences, Young Adult, Autoimmune Diseases of the Nervous System, Humans, Preschool, idiopathic basal ganglia calcification, business.industry, Biomarkers, Infant, Pediatrics, Perinatology and Child Health, Neurology (clinical), medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, business, Interferon type I
Abstract

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context., European Research Council (GA 309449: Fellowship to Y.J.C.), ERA-NET Neuron (MR/M501803/1), and a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” (ANR-10-IAHU-01)

Published
2017
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34. Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

Author

Keri Ramsey, Dennis J. Dlugos, Bodo Laube, Carolien G.F. de Kovel, Deborah Bartholdi, Carla Mendonça, Marine Lebrun, Doriana Misceo, Johannes R. Lemke, Christeen Ramane J. Pedurupillay, Vinodh Narayanan, Petter Strømme, Thomas Dorn, Carolina Courage, Ingo Helbig, Peter De Jonghe, Joaquim Sa, Jacques L. Michaud, Heinrich Vogt, Deepa S. Rajan, Peter Nürnberg, Emilia K. Bijlsma, Vikas Bhambhani, Claudia A. L. Ruivenkamp, Sarah Weckhuysen, Steffen Syrbe, Newell Belnap, Bobby P. C. Koeleman, Isabelle Schrauwen, Catherine Badens, Amélie Piton, Delphine Héron, Amy Goldstein, Gerhard Kurlemann, Dennis Lal, Bernd A. Neubauer, Holger Thiele, Tiffany Busa, Georgianne L. Arnold, Emily S. Doherty, Julia Hentschel, Saskia Biskup, Mariëtte J.V. Hoffer, Helle Hjalgrim, Henrike O. Heyne, Christel Depienne, Ryan Richholt, Christine Francannet, Caroline Nava, Rikke S. Møller, Erik Riesch, Eirik Frengen, Kirsten Geider, Katherine L. Helbig, Mathieu Milh, Hannah Schütz, Katia Hardies, Linda De Meirleir, University of Calgary, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Medical Genetics Laboratory, Cologne Center for Genomics, University of Cologne, Department of Neuropediatrics, Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Children's Hospital of Pittsburgh, Department of Molecular and Developmental Genetics (VIB11), Flanders institute of biotechnology, Institute Born-Bunge, University of Antwerp (UA), Antwerp University Hospital [Edegem] (UZA), Neurogenetics Group, Pediatric neurology- metabolic diseases, UZ Brussel, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Department of Neurodegenerative Diseases, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Children’s Hospital of Philadelphia (CHOP ), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cologne Center for Genomics (CCG), University of Cologne, Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], CHU Saint-Etienne, Reproduction and Genetics, Neurogenetics, Clinical sciences, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-IFR70-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière]

Subjects
0301 basic medicine, Movement disorders, Clinical Neurology, Intellectual disability, Diseases, Consanguinity, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Subunits, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Journal Article, Aphasia, Missense mutation, Genetics, Mutation, Diversity, Disorders, Cortical blindness, GRIN1, Focal epilepsy, Binding, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, biology.protein, Neurology (clinical), Human medicine, medicine.symptom, De-novo mutations, 030217 neurology & neurosurgery
Abstract

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders. Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France).

Published
2016
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35. Characterization of X Chromosome Inactivation Using Integrated Analysis of Whole-Exome and mRNA Sequencing

Author

David Craig, Isabelle Schrauwen, Keri Ramsey, Jason J. Corneveaux, Jeffrey M. Trent, Szabolcs Szelinger, Matthew J. Huentelman, Ashley L. Siniard, Ahmet Kurdoglu, Ivana Malenica, and Vinodh Narayanan

Subjects
Molecular biology, lcsh:Medicine, Gene Expression, Allelic Imbalance, Sequencing techniques, X Chromosome Inactivation, High throughput sequencing, Exome, lcsh:Science, Child, X-linked recessive inheritance, X chromosome, Sequence Deletion, Genetics, Multidisciplinary, High-Throughput Nucleotide Sequencing, RNA sequencing, Genomics, DNA methylation, Dosage Compensation, Epigenetics, Female, Engineering sciences. Technology, Transcriptome Analysis, Research Article, Next-Generation Sequencing, Adolescent, Biology, Research and Analysis Methods, Gene dosage, X-inactivation, Young Adult, Humans, Gene Regulation, Computer Simulation, RNA, Messenger, Allele, Chromosomes, Human, X, Biology and life sciences, Sequence Analysis, RNA, lcsh:R, Computational Biology, Genome Analysis, MRNA Sequencing, Molecular biology techniques, Genetics of Disease, lcsh:Q, Nervous System Diseases
Abstract

In females, X chromosome inactivation (XCI) is an epigenetic, gene dosage compensatory mechanism by inactivation of one copy of X in cells. Random XCI of one of the parental chromosomes results in an approximately equal proportion of cells expressing alleles from either the maternally or paternally inherited active X, and is defined by the XCI ratio. Skewed XCI ratio is suggestive of non-random inactivation, which can play an important role in X-linked genetic conditions. Current methods rely on indirect, semi-quantitative DNA methylation-based assay to estimate XCI ratio. Here we report a direct approach to estimate XCI ratio by integrated, family-trio based whole-exome and mRNA sequencing using phase-by-transmission of alleles coupled with allele-specific expression analysis. We applied this method to in silico data and to a clinical patient with mild cognitive impairment but no clear diagnosis or understanding molecular mechanism underlying the phenotype. Simulation showed that phased and unphased heterozygous allele expression can be used to estimate XCI ratio. Segregation analysis of the patient's exome uncovered a de novo, interstitial, 1.7 Mb deletion on Xp22.31 that originated on the paternally inherited X and previously been associated with heterogeneous, neurological phenotype. Phased, allelic expression data suggested an 83: 20 moderately skewed XCI that favored the expression of the maternally inherited, cytogenetically normal X and suggested that the deleterious affect of the de novo event on the paternal copy may be offset by skewed XCI that favors expression of the wild-type X. This study shows the utility of integrated sequencing approach in XCI ratio estimation.

Published
2014

36. Scavenger Chemokine (CXC Motif) Receptor 7 (CXCR7) Is a Direct Target Gene of HIC1 (Hypermethylated in Cancer 1)*

Author

Agnès Bégue, Brian R. Rood, Majid Touka, Sébastien Pinte, Dietrich A. Stephan, Mathias Jenal, Cateline Guérardel, Didier Monté, Capucine Van Rechem, Keri Ramsey, Mario P. Tschan, and Dominique Leprince

Subjects
Chromatin Immunoprecipitation, Tumor suppressor gene, Genetic Vectors, Molecular Sequence Data, Kruppel-Like Transcription Factors, Down-Regulation, C-C chemokine receptor type 6, CCR8, Biology, Biochemistry, Adenoviridae, Chemokine receptor, Sirtuin 1, Cell Line, Tumor, Humans, Sirtuins, Transcription, Chromatin, and Epigenetics, RNA, Messenger, Promoter Regions, Genetic, Molecular Biology, Conserved Sequence, Phylogeny, Cell Proliferation, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Receptors, CXCR, Osteosarcoma, Base Sequence, Cell Biology, Fibroblasts, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Alcohol Oxidoreductases, Cancer research, Corepressor, Chromatin immunoprecipitation, CCL21, Genes, Neoplasm
Abstract

The tumor suppressor gene HIC1 (Hypermethylated in Cancer 1) that is epigenetically silenced in many human tumors and is essential for mammalian development encodes a sequence-specific transcriptional repressor. The few genes that have been reported to be directly regulated by HIC1 include ATOH1, FGFBP1, SIRT1, and E2F1. HIC1 is thus involved in the complex regulatory loops modulating p53-dependent and E2F1-dependent cell survival and stress responses. We performed genome-wide expression profiling analyses to identify new HIC1 target genes, using HIC1-deficient U2OS human osteosarcoma cells infected with adenoviruses expressing either HIC1 or GFP as a negative control. These studies identified several putative direct target genes, including CXCR7, a G-protein-coupled receptor recently identified as a scavenger receptor for the chemokine SDF-1/CXCL12. CXCR7 is highly expressed in human breast, lung, and prostate cancers. Using quantitative reverse transcription-PCR analyses, we demonstrated that CXCR7 was repressed in U2OS cells overexpressing HIC1. Inversely, inactivation of endogenous HIC1 by RNA interference in normal human WI38 fibroblasts results in up-regulation of CXCR7 and SIRT1. In silico analyses followed by deletion studies and luciferase reporter assays identified a functional and phylogenetically conserved HIC1-responsive element in the human CXCR7 promoter. Moreover, chromatin immunoprecipitation (ChIP) and ChIP upon ChIP experiments demonstrated that endogenous HIC1 proteins are bound together with the C-terminal binding protein corepressor to the CXCR7 and SIRT1 promoters in WI38 cells. Taken together, our results implicate the tumor suppressor HIC1 in the transcriptional regulation of the chemokine receptor CXCR7, a key player in the promotion of tumorigenesis in a wide variety of cell types.

Published
2009

37. Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set

Author

Donald E. Schmechel, Eric M. Reiman, Dietrich A. Stephan, Richard J. Caselli, Walter A. Kukull, Andrew Grover, John C. Morris, Joseph Rogers, Thomas G. Beach, Christine M. Hulette, Diego Mastroeni, Winnie S. Liang, Daniel W. McKeel, Keri Ramsey, and Travis Dunckley

Subjects
Physiology, Middle temporal gyrus, Population, Hippocampus, Plaque, Amyloid, Biology, Bioinformatics, Article, Amyloid beta-Protein Precursor, Alzheimer Disease, Cortex (anatomy), Databases, Genetic, Genetics, medicine, Humans, education, Laser capture microdissection, Aged, Neurons, education.field_of_study, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Brain, Reproducibility of Results, Neurofibrillary Tangles, Entorhinal cortex, medicine.anatomical_structure, Superior frontal gyrus, Gene Expression Regulation, Organ Specificity, Posterior cingulate, Neuroscience, Protein Kinases, Molecular Chaperones
Abstract

Alzheimer's Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world's population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regard to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource.

Published
2008

38. Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure.

Author

Daryl Pritchard, Susan Ceryak, Keri Ramsey, Travis O'Brien, Linan Ha, Jamie Fornsaglio, Dietrich Stephan, and Steven Patierno

Abstract

Certain hexavalent chromium [Cr(VI)] compounds are known genotoxic respiratory carcinogens, which induce apoptosis as a predominant mode of cell death. Selection of cells that are resistant to apoptosis may be a factor in tumour progression. We developed sub-populations of telomerase-transfected human fibroblasts (BJ-hTERT) that survived a 99% clonogenically lethal exposure to Cr(VI) (B-5Cr). B-5Cr cells were markedly resistant to apoptosis induced by several agents and exhibited increased clonogenic survival, especially at apoptogenic doses. B-5Cr cells did not exhibit altered cellular uptake of Cr(VI) and retained a normal p53 response to Cr(VI) exposure. We conducted large-scale gene expression analysis at different time-points after a secondary genotoxic Cr(VI) insult in B-5Cr and BJ-hTERT cells using Affymetrix Genechip® human genome arrays. Cr(VI) exposure led to differential regulation of many genes, which affect a diverse set of cellular activities such as transcription, signal transduction, stress response, cell adhesion, DNA repair, apoptosis and cell cycle modulation. We compared Cr(VI)-induced altered gene expression in the B-5Cr cells to that in the parental cells and identified 223, 147 and 204 genes with at least a two-fold difference in expression at 4, 8 and 18 h after exposure, respectively. Cluster analysis by gene function revealed altered expression of genes involved in apoptosis, cell cycle regulation and DNA repair. Our data suggest an alteration in gene expression that may favor cell survival and/or incomplete DNA repair after genotoxic exposure. Selection of cells with altered expression of these genes may constitute the early stages of tumour progression. [ABSTRACT FROM AUTHOR]

Published
2005

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