Case Report: De novo DDX3X mutation caused intellectual disability in a female with skewed X-chromosome inactivation on the mutant allele

Abstract

Skewed XCI plays an important role in the phenotypic heterogeneities of many X-linked disorders, even involving in diseases caused by XCI-escaping genes. DDX3X-related intellectual disability is more common in females and less common in males, who usually inherit from unaffected heterozygous mothers. As an X inactivation (XCI) escaping gene, the role of skewed XCI in the phenotype of DDX3X mutant female is unknown. Here we reported a DDX3X: c.694_711dup18 de novo heterozygous mutation in a female with intellectual disability on the maternal X chromosome on the basis of SNPs detected by PCR-sanger sequencing. AR assay revealed that the maternal mutant X chromosome was extremely inactivated in the proband. Using RNA sequencing and whole-exome sequencing, we quantified allelic read counts and allele-specific expression, and confirmed that the mutant X chromosome was inactive. Further, we verified that the mutant DDX3X allele had a lower expression level by RNA sequencing and RT-PCR, and the normal and mutated DDX3X expression accounted for respectively 70% and 30% of total. In conclusion, we found a symptomatic female with extreme skewing XCI in the DDX3X mutant allele. It was discovered that XCI in the mutant allele was insufficient to reverse the phenotype of DDX3X-related neurodevelopmental disorder. It contributed to a better understanding of the role of skewed XCI in phenotypic differences, which can aid in the genetic counseling and prenatal diagnosis of disorders in females with DDX3X defects.

Dandy-Walker Malformation in a Girl with DDX3X-Related Intellectual Disability

“…To date, more than 75 different variants have been reported in the DDX3X gene. Majority of these variants are clustered in the two helicase domains (ATP binding and C-terminal) which are crucial for the protein function [Moresco et al, 2021;Sun et al, 2022].…”

Identification and functional analysis of a novel de novo missense mutation located in the initiation codon of LAMP2 associated with early onset female Danon disease

“…Although current insight indicated that nonsense, frameshift, and large deletion/duplication mutations were associated with an early onset of Danon disease, whereas splicing and missense mutations showed a trend of a later disease onset (D'Souza et al, 2014 ), missense mutations located at the start codon confirmed as null mutations are associated with an early onset in our case. For X chromosome‐linked genetic disorders, highly skewed XCI (90% or higher) is increased in women with abnormal X chromosomes in a manner that preserves the normal X chromosome (or autosomal) dosage (Brown et al, 2001 ; Sun et al, 2022 ; Warburton et al, 2009 ; Xu et al, 2019 ). Skewed XCI in female patients associated with normal LAMP2 expression and normal clinical phenotype has been reported (Majer et al, 2012 ; Xu et al, 2019 ).…”