DDX3X-related neurodevelopmental disorder in males - presenting a new cohort of 19 males and a literature review

Abstract

DDX3X-related neurodevelopmental disorder is one of the most common monogenic causes of intellectual disability in females, with currently >1000 females diagnosed worldwide. In contrast, reports on affected males with DDX3X variants are scarce. The limited knowledge on this X-linked disorder in males hinders the interpretation of hemizygous DDX3X variants in clinical practice. In this study, we present a new cohort of 19 affected males (from 17 unrelated families) with (possibly) disease-causing DDX3X variants, for whom we collected clinical and molecular data. Additionally, we reviewed the existing literature on 13 males with DDX3X variants. The phenotype in males is diverse, including intellectual disability, speech/language delays, behavioural challenges and structural brain abnormalities. The vast majority of males have missense variants, including two recurrent variants (p.(Arg351Gln) and p.(Arg488Cys)). No truncating variants have been reported, consistent with the presumed embryonic lethality of complete loss-of-function of DDX3X in males. In our novel cohort, 6/17 variants are de novo in the affected male and 3/17 variants are de novo in the mother. This study provides significant insights in the genetic and phenotypic spectrum of males with DDX3X variants, by presenting the data of a combined cohort (n = 32) of novel and published individuals. Our data show that variants in DDX3X can cause an X-linked neurodevelopmental disorder in males, with unaffected or mildly affected carrier females. These findings will aid the interpretation of hemizygous missense variants in DDX3X and can guide clinical management and counselling, in particular with regard to recurrence risks in the respective families.

Fig. 1. Facial photographs and pedigrees of males with DDX3X variants.

A Facial photgraphs. B Pedigrees. All (relevant) tested family members are indicated by + (DDX3X variant present) or - (DDX3X variant absent) (noted as x/x in females for biallelic state).

Fig. 2. DDX3X variants in males.

A Visual representation of DDX3X transcript (MANE transcript; NM_001356.5) with variants predicted to affect splicing. B Linear representation of the DDX3X protein including the two helicase domains (extracted from Uniprot) with locations of missense variants annotated.