Prospective and detailed behavioral phenotyping in DDX3X syndrome

Abstract

Background DDX3X syndrome is a recently identified genetic disorder that accounts for 1–3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. Methods We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. Results Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype–phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. Limitations Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. Conclusion This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype–phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.

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

“…Finally, we ran three general linear models to explore whether genetic variant type influences commonly endorsed social and emotional features (autism characteristics, anxiety and SIBs) within the DDX3X group (Table 4 ). In all three models, we included age and adaptive ability as covariates, as participants with missense variants were on average older than those with protein-truncating variants (missense: mean age = 16.08 years, SE = 1.95; protein-truncating: mean age = 11.76 years, SE = 1.49), and, as has been reported previously (Tang et al, 2021 ), participants with missense variants had lower adaptive abilities than those with protein truncating variants (missense: mean VABS Composite = 43.71, SE = 4.79; protein truncating: mean VABS Composite = 58.77, SE = 4.04). Across all three models, variant type did not significantly predict levels of autism characteristics, anxiety, or SIBs.…”

“…Further, they reported that missense variants (changes to a single amino acid within the DDX3X protein) were associated with more severe clinical outcomes than protein truncating variants (changes to the length of the DDX3X protein, likely to result in reduced protein availability) across neuroanatomical, neurological, adaptive and behavioural domains. Elsewhere, Tang et al ( 2021 ) characterized behavioural profiles of 15 individuals (14 females) with DDX3X variants via systematic post-diagnostic assessments of intellectual and adaptive functioning, sensory processing, autism and behavioural comorbidities. Based on diagnostic clinical assessments, 80% of individuals with DDX3X variants met diagnostic criteria for ID, 60% for autism spectrum disorder, and 53% for attention deficit / hyperactivity disorder (ADHD).…”

“…In addition, 14% of individuals reported elevated anxiety above a likely clinically-relevant level. Comparing behavioural profiles across variant types revealed that missense variants and in-frame deletions were associated with poorer language, motor and adaptive outcomes compared to protein-truncating variants (Tang et al, 2021 ). Further, a smaller proportion of individuals with protein-truncating variants met diagnostic criteria for autism, although this difference was not significant and may reflect expected differences between groups with different adaptive abilities.…”

Comorbidities in autism spectrum disorder and their etiologies

“…The observations of higher rates of certain health conditions in ASD [2][3][4][5][6][7][8][9] suggest the possibility of a shared etiology between these different comorbidities and ASD. This possibility is substantiated by the observations that some ASD-associated risk genes often have pleiotropic effects on traits otherwise not seen in the majority of individuals with ASD (e.g., DDX3X and gait disturbance 15 ). Despite this evidence, in non-syndromic forms of ASD, potential etiological overlaps between ASD and its comorbidities have not been systematically explored.…”

Aberrant cortical development is driven by impaired cell cycle and translational control in aDDX3Xsyndrome model

“…DDX3X is X-linked, which likely explains the preponderance of female cases; although an increasing number of de novo and inherited DDX3X mutations are found in males (Kellaris et al 2018; Nicola et al 2019). While DDX3X syndrome is characterized by ID, these individuals also commonly present with muscle tone and gait abnormalities, language deficits, abnormal brain MRIs (particularly white matter loss and corpus callosum defects), and many are diagnosed with ASD (Johnson-Kerner et al 1993; Lennox et al 2020; Tang et al 2021). Indeed, DDX3X mutations have been identified in ASD cohorts, and DDX3X is considered a high-confidence Autism gene (Iossifov et al 2014; RK et al 2017; Takata et al 2018; Ruzzo et al 2019).…”