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

• Published in: Clinical genetics 2024-12, Vol.106 (6), p.757-763
• Main Authors: Malbos, Marlène, Vera, Gabriella, Sheth, Harsh, Schnur, Rhonda E., Juven, Aurélien, Brehin, Anne‐Claire, Sheth, Jayesh, Gandhi, Ajit, Shapiro, Faye L., Bruel, Ange‐Line, Marguet, Florent, Begtrup, Amber, Monaghan, Kristin G., Safraou, Hana, Brasseur‐Daudruy, Marie, Mau‐Them, Frédéric Tran, Duffourd, Yannis, Faivre, Laurence, Thauvin‐Robinet, Christel, Benke, Paul J., Philippe, Christophe
• Format: Article
• Language: English
• Subjects: Alleles; Arthrogryposis; Arthrogryposis - genetics; Arthrogryposis - pathology; arthrogryposis multiplex congenital‐4; Child, Preschool; Consanguinity; Corpus callosum; Epilepsy; Excitotoxicity; Female; Genes, Recessive; Genetic Predisposition to Disease; Humans; Infant; Kinases; Loss of Function Mutation - genetics; loss‐of‐function; Male; missense; Mutation - genetics; Nervous system; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - pathology; Neurological complications; Pedigree; Phenotype; Phenotypes; Protein transport; Proteins; SCYL2
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.14608

SCY1‐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. We describe two affected individuals with arthrogryposis multiplex congenita‐4 with SCYL2 bi‐allelic loss‐of‐function variants, and two individuals homozygous for SCYL2 missense variants presenting with developmental delay only. Our study confirms the association of SCYL2 with arthrogryposis multiplex congenita‐4 and suggests a milder phenotype can occur.