Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder

Authors

Semino F^1,2, Schröter J¹, Willemsen MH³, Bast T^4,5, Biskup S^6,7, Beck-Woedl S⁸, Brennenstuhl H⁹, Schaaf CP¹⁰, Kölker S⁹, Hoffmann GF⁹, Haack TB^8,11, Syrbe S¹

Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Institute for Physiology and Pathophysiology, Medical Faculty, University of Heidelberg, Heidelberg, Germany.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Epilepsy Center Kork, 77694, Kehl, Germany.
Medical Faculty of the University of Freiburg, 77694, Kehl, Germany.
Praxis für Humangenetik Tübingen, 72076, Tuebingen, Germany.
CEGAT GmbH, 72076, Tuebingen, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Division of Neuropediatrics and Inherited Metabolic Diseases, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Center for Rare Diseases, University of Tübingen, Tübingen, Germany.

Abstract

SYNCRIP encodes for the Synaptotagmin-binding cytoplasmic RNA-interacting protein, involved in RNA-binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants. All individuals had ID. Autistic features were observed in two. One individual showed myoclonic-atonic epilepsy. Neuroradiological features comprised periventricular nodular heterotopia and widening of subarachnoid spaces. Two frameshift variants in the more severely affected individuals, likely result in haploinsufficiency. The third missense variant lies in the conserved RRM 2 domain likely affecting RNA-binding. Our findings support the importance of RRM domains for SYNCRIP functionality and suggest genotype-phenotype correlations. Our study provides further evidence for a SYNCRIP-associated NDD characterized by ID and ASD sporadically accompanied by malformations of cortical development and myoclonic-atonic epilepsy. This article is protected by copyright. All rights reserved.

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