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Case Reports
. 2024 Dec;106(6):757-763.
doi: 10.1111/cge.14608. Epub 2024 Aug 21.

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

Marlène Malbos  1   2 , Gabriella Vera  3 , Harsh Sheth  4 , Rhonda E Schnur  5 , Aurélien Juven  1   2 , Anne-Claire Brehin  3 , Jayesh Sheth  4 , Ajit Gandhi  4 , Faye L Shapiro  5 , Ange-Line Bruel  2   6 , Florent Marguet  3 , Amber Begtrup  7 , Kristin G Monaghan  7 , Hana Safraou  2   6 , Marie Brasseur-Daudruy  8 , Frédéric Tran Mau-Them  2   6 , Yannis Duffourd  2 , Laurence Faivre  1   2 , Christel Thauvin-Robinet  1   2 , Paul J Benke  9 , Christophe Philippe  2   6   10
Affiliations
Case Reports

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

Marlène Malbos et al. Clin Genet. 2024 Dec.

Abstract

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.

Keywords: SCYL2; arthrogryposis; arthrogryposis multiplex congenital‐4; loss‐of‐function; missense.

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References

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