Genet Med. 2024 Sep 25:101282. doi: 10.1016/j.gim.2024.101282. Online ahead of print.
ABSTRACT
PURPOSE: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well phenotyped and highly consanguineous (16%) NDD cohort.
METHODS: We employed chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202) and long-read genome sequencing to identify genetic etiology. Deep clinical multi-variate data was coupled with genomic variants for stratification analysis.
RESULTS: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (p<0.01) compared to those from non-consanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified two recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift.
CONCLUSION: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.
PMID:39342494 | DOI:10.1016/j.gim.2024.101282
