A Genotype/Phenotype Study of -Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in , including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in . We performed deep phenotyping and collected the clinical information and molecular data of these individuals' family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the -related neurodevelopmental disorder and suggests the pathogenicity of certain dominant missense variants.