Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder
Cuinat, Silvestre; Nizon, Mathilde; Isidor, Bertrand; Stegmann, Alexander; van Jaarsveld, Richard H; van Gassen, Koen L; van der Smagt, Jasper J; Volker-Touw, Catharina M L; Holwerda, Sjoerd J B; Terhal, Paulien A; Schuhmann, Sarah; Vasileiou, Georgia; Khalifa, Mohamed; Nugud, Alaa A; Yasaei, Hemad; Ousager, Lilian Bomme; Brasch-Andersen, Charlotte; Deb, Wallid; Besnard, Thomas; Simon, Marleen E H; Amsterdam, Karin Huijsdens-van; Verbeek, Nienke E; Matalon, Dena; Dykzeul, Natalie; White, Shana; Spiteri, Elizabeth; Devriendt, Koen; Boogaerts, Anneleen; Willemsen, Marjolein; Brunner, Han G; Sinnema, Margje; De Vries, Bert B A; Gerkes, Erica H; Pfundt, Rolph; Izumi, Kosuke; Krantz, Ian D; Xu, Zhou L; Murrell, Jill R; Valenzuela, Irene; Cusco, Ivon; Rovira-Moreno, Eulàlia; Yang, Yaping; Bizaoui, Varoona; Patat, Olivier; Faivre, Laurence; Tran-Mau-Them, Frederic; Vitobello, Antonio; Denommé-Pichon, Anne-Sophie; Philippe, Christophe; Bezieau, Stéphane; Cogné, Benjamin
(2022) Genetics in medicine : official journal of the American College of Medical Genetics, volume 24, issue 8, pp. 1774 - 1780
(Article)
Abstract
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
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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.
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Keywords: Intellectual disability, Molecular genetics, Neurodevelopment, Spliceosome, SRRM2, Genetics(clinical), Journal Article
ISSN: 1098-3600
Publisher: Lippincott Williams and Wilkins
Note: Publisher Copyright: © 2022 American College of Medical Genetics and Genomics
(Peer reviewed)