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

Human Genomics
Georgios KellarisNicholas Katsanis

Abstract

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. 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. 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 cr...Continue Reading

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Citations

Feb 9, 2019·American Journal of Medical Genetics. Part a·Pantelis NicolaJill Clayton-Smith
Jul 6, 2019·Clinical Dysmorphology·Bryony BealHimanshu Goel
Jul 1, 2020·Italian Journal of Pediatrics·Liqin HuJungao Huang
Dec 16, 2020·Development·Mark PerfettoShuo Wei
Feb 26, 2021·Molecular Cancer·Jie MoBixiang Zhang
May 18, 2021·Molecular Autism·Lara TangDorothy E Grice
Aug 5, 2021·Biological Psychiatry·Andrea BoitnottSilvia De Rubeis

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