Phenotypic expansion in DDX3X - a common cause of intellectual disability in females

Abstract

De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.

Figure 1

Location of DDX3X variants identified in this study, Female individuals (25, 26, 27) ascertained through the BHCMG, and muscle biopsy results in Female 17 showing abnormal mitochondrial morphology. (A) Schematic view of the DDX3X exon–intron structure based on NM_001193416. Blue boxes represent exons and yellow fields represent introns. Exon number is listed below each exon. cDNA change is listed for each variant. (B) Schematic view of the DDX3X protein structure based on Snijders Blok et al.11 Amino acid change is listed for each variant. (C) Pedigree and Sanger tracings demonstrate de novo inheritance in three unrelated female probands. (D) Female 25 demonstrated synophrys, a broad nasal root with upturned nostrils, a long philtrum, and thin upper lip. Female 27 demonstrated cupped ears, a long philtrum, and a thin upper lip. (E–G) Muscle biopsy results in Female 17 (E) Skeletal muscle cross‐section showing mild variation in fiber size (H&E; magnification ×400). (F) Skeletal muscle cross‐section showing few fibers with mild subsarcolemmal increase in oxidative activity [cytochrome oxidase (long arrow) and NADH tetrazolium reductase (inset – arrow heads; magnifications ×400)]. (G) Electron microscopic images showing mild subsarcolemmal mitochondrial proliferation (long arrow) with inset in the upper corner showing pleomorphic abnormally elongated and irregularly shaped mitochondria (arrow heads). Variant color in (A) and (B): black, first reported in this study; purple, previously reported. The c.1304T>C (p.L435P) variant from Fetus 1 was not listed in (A) and (B).