Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder.

Autor:	Cuinat S; Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France. Electronic address: silvestre.cuinat@chu-nantes.fr., Nizon M; Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France; Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France., Isidor B; Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France; Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France., Stegmann A; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., van Jaarsveld RH; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., van Gassen KL; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., van der Smagt JJ; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Volker-Touw CML; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Holwerda SJB; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Terhal PA; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Schuhmann S; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany., Vasileiou G; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany., Khalifa M; Genetic Department, Dubai Health Authority, Latifa Women and Children Hospital, Dubai, United Arab Emirates., Nugud AA; Genetic Department, Dubai Health Authority, Latifa Women and Children Hospital, Dubai, United Arab Emirates., Yasaei H; Dubai Genetics Center, Pathology and Genetics Department, Dubai Health Authority, Dubai, United Arab Emirates., Ousager LB; Department of Clinical Genetics & Human Genetics, Odense University Hospital, University of Southern Denmark, Odense, Denmark; Department of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark., Brasch-Andersen C; Department of Clinical Genetics & Human Genetics, Odense University Hospital, University of Southern Denmark, Odense, Denmark; Department of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark., Deb W; Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France; Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France., Besnard T; Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France; Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France., Simon MEH; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Amsterdam KH; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Verbeek NE; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Matalon D; Department of Pediatric, Division of Medical Genetics, Stanford University and Health Care, Palo Alto, CA., Dykzeul N; Department of Pediatric, Division of Medical Genetics, Stanford University and Health Care, Palo Alto, CA., White S; Department of Pediatric, Division of Medical Genetics, Stanford University and Health Care, Palo Alto, CA., Spiteri E; Department of Pediatric, Division of Medical Genetics, Stanford University and Health Care, Palo Alto, CA., Devriendt K; Center for Human Genetics, University Hospital Leuven, KU Leuven, O&N I Herestraat 49, Leuven, Belgium., Boogaerts A; Center for Human Genetics, University Hospital Leuven, KU Leuven, O&N I Herestraat 49, Leuven, Belgium., Willemsen M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., Brunner HG; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., Sinnema M; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., De Vries BBA; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Gerkes EH; University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands., Pfundt R; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Izumi K; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA., Krantz ID; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA., Xu ZL; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA., Murrell JR; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA., Valenzuela I; Department of Clinical and Molecular Genetics, Hospital Vall d'Hebron, Barcelona, Spain., Cusco I; Department of Clinical and Molecular Genetics, Hospital Vall d'Hebron, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain., Rovira-Moreno E; Department of Clinical and Molecular Genetics, Hospital Vall d'Hebron, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain., Yang Y; AiLife Diagnostics, Pearland, TX., Bizaoui V; Clinical Genetics and Neurodevelopmental Disorders, Centre Hospitalier de l'Estran, Pontorson, France., Patat O; Department of Medical Genetics, Toulouse University Hospital, Toulouse, France., Faivre L; Centre de référence Anomalies du Développement et Syndromes malformatifs, FHU-TRANSLAD, GAD, CHU Dijon et Université de Bourgogne, Dijon, France; Inserm UMR1231, GAD, Université de Bourgogne, Dijon, France., Tran-Mau-Them F; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; Inserm UMR1231, GAD, Université de Bourgogne, Dijon, France., Vitobello A; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; Inserm UMR1231, GAD, Université de Bourgogne, Dijon, France., Denommé-Pichon AS; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; Inserm UMR1231, GAD, Université de Bourgogne, Dijon, France., Philippe C; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; Inserm UMR1231, GAD, Université de Bourgogne, Dijon, France., Bezieau S; Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France; Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France., Cogné B; Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France; Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France. Electronic address: benjamin.cogne@chu-nantes.fr.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Aug; Vol. 24 (8), pp. 1774-1780. Date of Electronic Publication: 2022 May 14.
DOI:	10.1016/j.gim.2022.04.011
Abstrakt:	Purpose: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease. Methods: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher. Results: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present. Conclusion: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease. Competing Interests: Conflict of Interest This work was carried out within the framework of Nantes University Medical Center activity without additional funding. One patient was diagnosed in the context of work in a private company (AiLife Diagnostics, Pearland, Texas). The other authors declare no conflicts of interest. (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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