P523: The NeuroDev Study: Genetic characterization of neurodevelopmental disorders in African populations

Document Type



Institute for Human Development


Introduction: Genetic association studies have made significant contributions to our understanding of the etiology of neurodevelopmental disorders (NDDs). However, the vast majority of these studies have focused on populations of European ancestry, and few include individuals from the African continent, creating substantial gaps in our understanding of the expression and variability of such disorders. Further, individuals of African ancestry are less likely to receive accurate genetic diagnoses and benefit from advances in genomic science and medicine. The NeuroDev study aims to address this diversity gap through detailed phenotypic and genetic characterization of children with NDDs from South Africa and Kenya. Here, we present the genetic findings from the NeuroDev pilot study, which consists of the study’s first 99 parent-child trios.

Methods: Exome sequencing and data processing were performed by the Genomics Platform at the Broad Institute of MIT and Harvard, and the resulting data was uploaded to the seqr platform for analysis. A standard analysis protocol, which involves both de novo/dominant and recessive searches, was deployed across all trios to identify potential causal variants. When evaluating variants in established disease genes, NeuroDev phenotype data was assessed for possible consistencies with known clinical presentations for that gene, bearing in mind potential deviations from expectation due to ancestry. Genes not yet associated with a well-established human disease were evaluated using a variety of sources of evidence, and candidate variants were shared with the Matchmaker Ex- change (MME) network to identify additional cases with similar genotypic and phenotypic profiles. Potential causal variants were subjected to rigorous evaluation of the evidence for pathogenicity following the ACMG/AMP guidelines, and variants meeting pathogenic or likely pathogenic (P/LP) criteria in South African probands were nominated for clinical validation and return to interested families.

Results: Exome sequencing analysis identified P/LP variants in 22 of the 99 cases. A total of 13 (17%) of the 75 cases from South Africa were found to have P/ LP variants eligible for return, including 6 single nucleotide variants (SNVs) or indels and 7 copy number variants (CNVs) impacting established NDD genes or cytogenetic regions. Of the 24 Kenyan cases, 9 (38%) were solved with P/LP variants, including 6 SNVs and 3 CNVs. In addition to the solved cases, 14 cases were found to have suspicious variants of uncertain significance (VUS) in candidate disease genes, which were submitted to MME. Matches were made for 7 of the 14 submitted candidates, each of which will be included in collaborative case series reports on the genes of interest. These variants may be reclassified in the future after re-evaluation of the evidence collected for these emerging gene-disease associations.

Conclusion: The NeuroDev study is making progress towards addressing the diversity gap in studies of the genetic etiology of neurodevelopmental disorders. The results of the first 99 trios demonstrate the potential for genetic characterization and rare disease discovery in an African context. Additionally, the NeuroDev trio pilot data is now the largest African NDD collection for which genetic and phenotypic data are publicly available to the research community, through the National Human Genome Research Institute Analysis Visualization and Informatics Lab-space (AnVIL) controlled access data repository. Over the course of the next few years, the NeuroDev study will, in total, perform exome sequencing and share data for approximately 2,000 children with NDDs, which will be of significant benefit to the global genetics community.

Publication (Name of Journal)

Genetics in Medicine Open