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.

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Background: Activity dependent neuroprotective protein (ADNP) syndrome is one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability, however, the phenotypes remain poorly described. Here we examine the sensory reactivity phenotype in children and adolescents with ADNP syndrome. Methods: Twenty-two individuals with ADNP syndrome received comprehensive clinical evaluations including standardized observations, caregiver interviews, and questionnaires to assess sensory reactivity symptoms. Relationships between sensory symptoms and age, sex, ASD, IQ, and adaptive behavior were examined. Genotype-phenotype correlations with the recurrent p.Tyr719* variant were also explored. Results: Sensory reactivity symptoms were observed and reported in all participants. A syndrome-specific phenotype was identified, characterized by high levels of sensory seeking across tactile, auditory, and visual domains. Tactile hyporeactivity, characterized by pain insensitivity, was reported in the majority of participants. Sensory symptoms were identified across individuals regardless of age, sex, IQ, adaptive ability, genetic variant, and most importantly, ASD status. No significant differences were identified between participants with and without the recurrent p.Tyr719* variant on any sensory measure. Conclusions: Sensory reactivity symptoms are a common clinical feature of ADNP syndrome. Quantifying sensory reactivity using existing standardized measures will enhance understanding of sensory reactivity in individuals with ADNP syndrome and will aid in clinical care. The sensory domain may also represent a promising target for treatment in clinical trials.

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Large‐scale genomic studies have identified over 100 genes associated with autism spectrum disorder (ASD); however, important phenotypic variables are captured inconsistently. In many cases, the resources required for comprehensive characterization hinder the feasibility of collecting critical information, such as intellectual ability. Thus, electronic collection of important phenotypes would greatly facilitate large‐scale data collection efforts. This study assessed the utility of two electronic assessments as a proxy of cognitive ability relative to clinician‐administered cognitive assessments. Ninety‐two participants completed the study, including individuals with ASD (probands, n = 19), parents of probands (n = 46), and siblings without ASD (n = 27). Participants were administered the electronic‐Peabody Picture Vocabulary Test, Fourth Edition (e‐PPVT‐4), an electronic visual reasoning (VR) test, and a clinician‐administered Wechsler Abbreviated Scales of Intelligence, Second Edition (WASI‐II). Probands also completed a full, in‐person, cognitive assessment and Vineland Adaptive Behavior Scales, 2nd Edition. Correlations between scores on electronic and clinician‐administered measures were examined. Classification accuracy of individual scores based on 95% confidence intervals and score range (below average, average, above average) were also assessed. Moderate to strong correlations were identified between both electronic measures and the clinician‐administered WASI‐II (ρ = 0.606–0.712). Mean difference between standard scores ranged from 10.7 to 14.8 for the cohort. Classification accuracy based on WASI‐II 95% confidence interval was consistently low (27.5%–47.3%). Classification accuracy by score range (below average, average, above average) was variable, ranging from 33% to 86% for probands. All participants unable to complete the electronic assessments met DSM‐5 criteria for intellectual disability. e‐PPVT‐4 and VR scores were strongly correlated with scores on the WASI‐II full‐scale IQ (ρ = 0.630, 0.712), indicating utility of these measures at the group level in large‐scale genomic studies. However, the poor precision of measurement across both measures suggests that the e‐PPVT‐4 and VR are not useful alternatives to in‐person testing for the purpose of clinical assessment of an individual's IQ score. Lay Summary Large‐scale studies designed to identify genes associated with autism have been successful in identifying over 100 genes. However, important clinical information about participants with autism and their family members is often missed—including cognitive functioning. Cognitive testing requires in‐person administration by a trained clinician and therefore can be burdensome and often reduces feasibility of diverse samples. Here, we assessed whether electronic assessments could take the place of in‐person cognitive testing. We found that at the group level, for large‐scale studies, electronic measures added valuable information; however, they were not accurate enough to be used on an indivi...