Social and emotional characteristics of girls and young women with DDX3X-associated intellectual disability: a descriptive and comparative study

Abstract

DDX3X variants are a common cause of intellectual disability (ID) in females, and have been associated with autism spectrum disorder and emotional-behavioural difficulties. In this study, we compared phenotypic data for 23 females with DDX3X variants, to 23 females with ID and other genetic diagnoses. We found a wide range of adaptive, social and emotional function within the DDX3X group. Autism characteristics did not differ between DDX3X and comparison groups, while levels of anxiety and self-injurious behaviour (SIB) were significantly higher in the DDX3X group. Within the DDX3X group, adaptive function, autism characteristics, anxiety and SIB scores were positively correlated, with evidence for group-specific associations with SIB. Future work is warranted to explore the multilevel mechanisms contributing to social and emotional development in individuals with DDX3X variants.

Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation

“…The proportion of likely benign/benign, likely pathogenic/pathogenic and VUS are plotted when variant classification is performed with and without incorporating the SGE data. C) Vineland composite scores for individuals with DDX3X-related neurodevelopmental disorder carrying a protein-truncating variant (PTV) or a missense or in-frame variant (M/IF) in three existing clinical phenotyping studies 20,35,36 . D) Vineland composite scores for individuals with DDX3X-related neurodevelopmental disorder carrying fast-depleting and slow-depleting variants.…”

“…To investigate whether there are differences in the severity of intellectual disability between DDX3X-related NDD probands who carry SGE-fast and SGE-slow-depleting variants we identified 61 probands who had undergone assessment via the Vineland Adaptive Behaviour Scales 41, 42 across three studies 20, 35, 36 . No difference in global adaptive function (Vineland Adaptive Behavior Composite score) was observed between individuals carrying missense variants and those carrying protein-truncating variants (PTVs) (Fig.4C).…”

“…Such factors will affect variant expressivity and may obfuscate identification of genotype-phenotype relationships. Previous studies have suggested that patients with missense variants in DDX3X have reduced adaptive ability and a more severe clinical phenotype than those with protein-truncating variants 20, 36 . However, in this larger meta-analysis, we see no evidence for different adaptive ability between patients carrying missense versus PTV variants (Fig.4Di).…”

“…Such factors will affect variant expressivity and may obfuscate identification of genotype-phenotype relationships. Previous studies have suggested that patients with missense variants in DDX3X have reduced adaptive ability and a more severe clinical phenotype than those with protein-truncating variants 20,36 .…”

“…However, we were not able to discern any phenotypic differences between patients carrying fast and slow-depleting variants, suggesting that different kinetics in short-term culture may not be biologically meaningful in the context of organismal neurodevelopment over years. Alternatively, we may lack power to discern such effects, as most phenotyping studies remain small, employ disparate neuropsychometric tests and not all patients are uniformly assessed 11,20,35,36 . It is also notable that DDX3X escapes X-inactivation to a variable degree between individuals [56][57][58] , and a high incidence of severe skewing of X-inactivation has been observed in patients with DDX3X-related neurodevelopmental disorder 11,22 .…”