SCYL2‐related autosomal recessive neurodevelopmental disorders: Arthrogryposis multiplex congenita‐4 and beyond?

Author:

Malbos Marlène12,Vera Gabriella3,Sheth Harsh4ORCID,Schnur Rhonda E.5,Juven Aurélien12,Brehin Anne‐Claire3,Sheth Jayesh4,Gandhi Ajit4,Shapiro Faye L.5,Bruel Ange‐Line26ORCID,Marguet Florent3,Begtrup Amber7,Monaghan Kristin G.7,Safraou Hana26,Brasseur‐Daudruy Marie8,Mau‐Them Frédéric Tran26,Duffourd Yannis2,Faivre Laurence12,Thauvin‐Robinet Christel12,Benke Paul J.9,Philippe Christophe2610

Affiliation:

1. CRMRs "Anomalies du Développement et syndromes malformatifs" et "Déficiences Intellectuelles de causes rares", FHU‐TRANSLAD, CHU Dijon Bourgogne Dijon France

2. Laboratoire de Génomique Médicale, UF Innovation en diagnostic génomique des maladies rares CHU Dijon Bourgogne Dijon France

3. Department of Pathology, Department of Genetics and Reference Center for Developmental Abnormalities Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen Rouen France

4. FRIGE's Institute of Human Genetics Ahmedabad India

5. Cooper Medical School of Rowan University/Cooper University Health Care Camden New Jersey USA

6. Inserm UMR1231 GAD, Université de Bourgogne‐Franche Comté, FHU TRANSLAD Dijon France

7. GeneDx Gaithersburg Maryland USA

8. Radiologie pédiatrique CHU de Rouen Rouen France

9. Division of Clinical Genetics Joe DiMaggio Children's Hospital Hollywood Florida USA

10. Laboratoire de Génétique CHR Metz‐Thionville, Hôpital Mercy Metz France

Abstract

AbstractSCY1‐like protein 2 (SCYL2) is a member of the SCY1‐like pseudokinase family which regulates secretory protein trafficking. It plays a crucial role in the nervous system by suppressing excitotoxicity in the developing brain. Scyl2 knockout mice have excess prenatal mortality and survivors show severe neurological dysfunction. Bi‐allelic loss‐of‐function (LOF) variants in SCYL2 were recently associated with arthrogryposis multiplex congenita‐4 (AMC4) following the report of 6 individuals from two consanguineous unrelated families. The AMC4 phenotype described included severe arthrogryposis, corpus callosum agenesis, epilepsy and frequently, early death. We describe here two additional similarly affected individuals with AMC4, including one diagnosed in the prenatal period, with bi‐allelic LOF variants in SCYL2, and two individuals homozygous for missense variants in the protein kinase domain of SCYL2 and presenting with developmental delay only. Our study confirms the association of SCYL2 with AMC4 and suggests a milder phenotype can occur, extending the phenotypic spectrum of autosomal recessive SCYL2‐related disorders.

Funder

European Commission

Publisher

Wiley

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