To characterize differences in neurodevelopmental outcomes by sex and mutation type among pediatric patients with ZC4H2-Associated Rare Disorders (ZARD).

ZARD comprises a spectrum of X-linked syndromes caused by pathogenic variants in the ZC4H2 gene, which encodes a zinc-finger protein essential for spinal cord development. Animal studies show ZC4H2 mutations impair synaptic plasticity and long-term potentiation, mechanisms vital for learning and memory. Prior studies highlight sex differences and genotype–phenotype correlations in individuals with ZARD; however, characterization of neurodevelopmental profiles remains limited. Adaptive behavior—encompassing conceptual, social, and practical skills needed for independent functioning—offers a useful framework for assessing neurodevelopmental differences. This study examines sex- and mutation-associated differences in adaptive behavior among individuals with ZARD.

The ZARD Natural History Study is a prospective, longitudinal study following participants with confirmed ZC4H2 pathogenic variants at six-month intervals. This analysis focuses on data from the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), which measures communication, daily living, and socialization domains, with an optional motor skills domain. ANOVA and two-sample t-tests with unequal variances were used for analysis.

Forty participants completed baseline Vineland-3 assessments, and twenty-five completed a one-year follow-up evaluation. Females demonstrated significantly higher mean standard scores and large effect sizes in the Adaptive Behavior Composite (p=0.03, Cohen's d=0.78), particularly in communication (p=0.02, Cohen's d=0.76) and socialization (p=0.03, Cohen's d=0.76) domains. There were no significant differences between mutation types. Across all domains, mean change from baseline to one-year follow-up showed a negative trend, though differences were not significant by sex or mutation type.

Overall, participants demonstrated decline in adaptive behavior over time. Findings suggest sex-related differences in adaptive functioning among individuals with ZARD, with females more likely to show higher adaptive function, potentially informing prognosis and individualized intervention. Ongoing longitudinal follow-up will further clarify developmental trajectories and genotype–phenotype relationships in this rare neurodevelopmental disorder.