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Background  Intellectual disability (ID) is a common condition with a population prevalence frequency of 1–3% and an enrichment for males, driven in part by the contribution of mutant alleles on the X-chromosome. Among the more than 500 genes associated with ID,  DDX3X  represents an outlier in sex specificity. Nearly all reported pathogenic variants of  DDX3X  are de novo, affect mostly females, and appear to be loss of function variants, consistent with the hypothesis that haploinsufficiency at this locus on the X-chromosome is likely to be lethal in males.    Results  We evaluated two male siblings with syndromic features characterized by mild-to-moderate ID and progressive spasticity. Quad-based whole-exome sequencing revealed a maternally inherited missense variant encoding p.R79K in  DDX3X  in both siblings and no other apparent pathogenic variants. We assessed its possible relevance to their phenotype using an established functional assay for DDX3X activity in zebrafish embryos and found that this allele causes a partial loss of DDX3X function and thus represents a hypomorphic variant.    Conclusions  Our genetic and functional data suggest that partial loss of function of  DDX3X  can cause syndromic ID. The p.R79K allele affects a region of the protein outside the critical RNA helicase domain, offering a credible explanation for the observed retention of partial function, viability in hemizygous males, and lack of pathology in females. These findings expand the gender spectrum of pathology of this locus and suggest that analysis for  DDX3X  variants should be considered relevant for both males and females.    Electronic supplementary material  The online version of this article (10.1186/s40246-018-0141-y) contains supplementary material, which is available to authorized users.

human genomics

A hypomorphic inherited pathogenic variant in DDX3X causes male intellectual disability with additional neurodevelopmental and neurodegenerative features