De novo missense variants in are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

Objective: To determine the potential disease association between variants in and complex multisystem neurological and developmental delay phenotypes.

Methods: Here we describe a series of de novo missense variants in in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.

Results: encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.

Conclusion: These findings indicate that rare de novo variants in can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring variants may lead to a better understanding of the function of this ubiquitously expressed gene.