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.

Keywords: Autism; DDX3X syndrome; Developmental delay; Genotype–phenotype correlation; Intellectual disability.

Fig. 1

DDX3X variants. Top, variants in the cohort: protein-truncating variants (PTVs) are colored tan, while missense variants and in-frame deletions are colored blue. The male participant carries the p.Arg292Leu variant. Bottom, recurrent variants: variants reported at least three times in the literature and/or in ClinVar. The helicase ATP-binding and helicase C-terminal domains are shown as reported in Uniprot O00571

Fig. 2

Intellectual, adaptive and motor functioning. a Frequency histograms of verbal, nonverbal, and fullscale developmental quotients (VDQ, NVDQ, DQ). b Frequency histograms of standard scores on domains of the Vineland-3: Adaptive Behavior Composite, Communication, Daily Living Skills, Socialization, and Motor (the Maladaptive Behavior domain is represented in Additional file 2: Fig. S1B). All plots show frequency (i.e., number of individuals) in each bin. Developmental delays of 25%, 50%, and 75% are indicated by dashed lines (a), while distribution of standard scores in typically developing individuals are shown as black lines (b), together with associated standard deviations (dashed lines). PTV, protein-truncating variant; missense, missense variant or in-frame deletion

Fig. 3

Psychiatric features. a Frequency histograms for the Autism Diagnostic Interview-Revised (ADI-R) Socialization, Communication, and Restricted/Repetitive Behavior (RRB) domains. Dashed lines represent the diagnostic threshold for ASD for each domain, with scores to the right surpassing the threshold. b Frequency histograms for the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) comparison score. Evidence levels for ASD are categorized as minimum-to-no evidence, low, moderate, and high evidence. c Frequency histograms for the Social Responsiveness Scale (SRS-2) total score. Total score has a mean of 50 and standard deviation of 10. d Frequency histograms for the Repetitive Behaviors Scale-Revised (RBS-R). Total scores have a minimum of 0 and maximum of 129. In all plots, higher scores indicate greater deficits. In c, d, distribution of standard scores in typically developing individuals are shown as black lines, together with associated standard deviations (dashed lines). PTV, protein-truncating variant; missense, missense variant or in-frame deletion

Fig. 4

Sensory reactivity. a Frequency histograms for the Sensory Assessment for Neurodevelopmental Disorders (SAND) hyperreactivity, hyporeactivity and sensory seeking domains. Distribution of standard scores in typically developing individuals are shown as black lines, together with associated standard deviations (dashed lines). b Average Z-scores for hyperreactivity, hyporeactivity, and seeking within visual, tactile, and auditory modalities. Z-scores have a mean of 0 where + 1 indicates 1 SD above the mean. PTV, protein-truncating variant; missense, missense variant or in-frame deletion

Fig. 5

Photographs of participants

Fig. 6

Phenotypic comparisons across variant classes. a Average scores for full scale DQ, nonverbal DQ, and verbal DQ, comparing the two variant types. b Average Vineland-3 standard scores, comparing the two variant types. c Average Vineland-3 v-scale scores, comparing the two variant types. Independent sample t-tests or chi-square analyses were performed to compare the neurobehavioral profiles across variant types. PTV, protein-truncating variant; missense, missense variant or in-frame deletion