CONSISTENT EFFECTS OF RARE EXONIC VARIANTS ON CHILD DEVELOPMENT AND COGNITIVE PERFORMANCE IN AFRICAN AND EUROPEAN POPULATIONS

Introduction Rare genetic variants contribute to childhood cognitive development but remain underexplored in African populations. Additionally, most cognitive assessment tools are developed in non-African contexts, raising concerns about their transferability. Here, we investigated the contribution of rare variant burden (RVB) to child development and cognitive performance in a South African sample. Methods Using data from 843 mother–child duos in the Drakenstein Child Health Study, we examined associations between RVB and developmental and cognitive outcomes assessed at age six using linear regression. RVB was defined as the exome-wide burden of rare putative loss-of-function variants, weighted by genic constraint (Shet). Development was assessed using the Early Learning Outcomes Measure (ELOM), designed for the South African context. Cognitive performance was assessed using the Wechsler IQ test (WPPSI-IV), developed in the USA. Results RVB was associated with poorer performance on both measures (pBonferroni < 0.025), explaining 0.63% and 0.82% of the variance in overall ELOM and WPPSI-IV scores, respectively. Effect sizes were comparable across assessments (βELOM = -1.21, βWPPSI-IV = -1.38 per Shet) and concordant with RVB effect on WISC IQ observed in a European ancestry British cohort at age 8 (βWISC = -1.15). Associations remained stable after adjustment for maternal RVB and environmental factors, including household income, education, and prenatal smoking and alcohol use. Conclusion These findings demonstrate a role for rare variants in childhood development and cognitive performance in African populations, with effect sizes comparable to European cohorts, supporting the generalisability of rare variant effects across diverse ancestries, environments and assessment tools.