Abstract
BackgroundIntellectual 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.ResultsWe 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.ConclusionsOur 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.
Highlights
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
We found that the DDX3X variant results in reduced DDX3X function, reinforcing the genetic hypothesis
Here, we describe the clinical phenotypes of two adult males who have a rare, maternally inherited missense allele of DDX3X, a major ID locus that to date has been associated with pathology almost exclusively in females
Summary
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. ID is more prevalent in males than females with a ratio of 1.3–1.4:1 [10], a gender bias partially reflective of the observation that numerous genes on the X-chromosome contribute to ID under an X-linked recessive paradigm [10]. Kellaris et al Human Genomics (2018) 12:11 studies of individuals, families, and populations with ID have led to the identification of more than 500 mutated genes, with some estimates predicting that number to exceed 1000, possibly reflective of the large number of transcripts expressed in and necessary for the development and maintenance of the central nervous system [10, 11]. Further phenotypic analyses have led to the appreciation of subtle phenotypic defects under a dosage model, in which males manifest the extreme range of pathology and females are partially protected [13]
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