Abstract
SCY1 Like Pseudokinase 2 (SCYL2) is a protein that regulates secretory protein trafficking and plays a pivotal role in neurodevelopment by attenuating excitotoxicity. Neurogenic arthrogryposis due to SCYL2 mutations, also known as arthrogryposis multiplex congenita 4 (AMC4), is a rare condition that presents with microcephaly, agenesis of the corpus callosum, optic atrophy, global developmental delay, and early lethality. We used whole-exome sequencing to identify pathogenic variants, DynaMut2 to determine the predicted effect on protein stability, and Western blot to investigate the effect on protein expression. We present two novel missense mutations in SCYL2 resulting in loss of function at the protein level in a pediatric case of AMC4, further highlighting the key role of SCYL2 in neuronal cell survival and healthy brain development. There is diversity in the pathological features among previously published cases of AMC4, most likely due to the nature of each mutation. This report summarizes the clinical data of all known patients with SCYL2 mutations.