SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

• DOI: 10.1016/j.ajhg.2023.03.016
• Publication Date: 2023-04-17T14:28:37Z
• Authors: Elke Bogaert; Aurore Garde; Thierry Gautier; Kathleen Rooney; Yannis Duffourd; Pontus LeBlanc; Emma van Reempts; Frederic Tran Mau...; Ingrid M. Wentzensen; Kit Sing Au; Kate Richardson; Hope Northrup; Vincent Gatinois; David Geneviève; Raymond J. Louie; Michael J. Lyons; Lone Walentin Lau...; Charlotte Brasch-...; Trine Maxel Juul; Fatima El It; Nathalie Marle; Patrick Callier; Raissa Relator; Sadegheh Haghshenas; Haley McConkey; Jennifer Kerkhof; Claudia Cesario; Antonio Novelli; Nicola Brunetti-P...; Michele Pinelli; Perrine Pennamen; Sophie Naudion; Marine Legendre; Cécile Courdier; Aurelien Trimouille; Martine Doco Fenzy; Lynn Pais; Alison Yeung; Kimberly Nugent; Elizabeth R. Roeder; Tadahiro Mitani; Jennifer E. Posey; Daniel Calame; Hagith Yonath; Jill A. Rosenfeld; Luciana Musante; Flavio Faletra; Francesca Montanari; Giovanna Sartor; Alessandra Vancini; Marco Seri; Claude Besmond; Karine Poirier; Laurence Hubert; Dimitri Hemelsoet; Arnold Munnich; James R. Lupski; Christophe Philippe; Christel Thauvin-...; Laurence Faivre; Bekim Sadikovic; Jérôme Govin; Bart Dermaut; Antonio Vitobello
• Keywords: Haploinsufficiency; Exonic splicing enhancer; Loss function

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds mRNA, regulating both constitutive alternative splicing. The complete loss of this proto-oncogene in mice embryonically lethal. Through international data sharing, we identified 17 individuals (10 females 7 males) with neurodevelopmental disorder (NDD) heterozygous germline variants, mostly de novo, including three frameshift nonsense seven missense two microdeletions within region 17q22 encompassing SRSF1. Only one family, novo origin could not be established. All featured recurrent phenotype developmental delay intellectual disability (DD/ID), hypotonia, neurobehavioral problems, variable skeletal (66.7%) cardiac (46%) anomalies. To investigate functional consequences performed silico structural modeling, developed an vivo splicing assay Drosophila, carried out episignature analysis blood-derived DNA from affected individuals. We found all loss-of-function 5 variants were pathogenic, leading activity correlating detectable specific methylation episignature. In addition, our orthogonal silico, vivo, epigenetics analyses enabled separation clearly pathogenic those uncertain significance. Overall, these results indicated haploinsufficiency responsible for syndromic NDD ID due partial SRSF1-mediated activity.