Abstract
Risk genes for Mendelian (single-gene) disorders (SGDs) are consistent across populations, but pathogenic risk variants that cause SGDs are typically population-private. The goal was to develop “QChip1,” an inexpensive genotyping microarray to comprehensively screen newborns, couples, and patients for SGD risk variants in Qatar, a small nation on the Arabian Peninsula with a high degree of consanguinity. Over 108 variants in 8445 Qatari were identified for inclusion in a genotyping array containing 165,695 probes for 83,542 known and potentially pathogenic variants in 3438 SGDs. QChip1 had a concordance with whole-genome sequencing of 99.1%. Testing of QChip1 with 2707 Qatari genomes identified 32,674 risk variants, an average of 134 pathogenic alleles per Qatari genome. The most common pathogenic variants were those causing homocystinuria (1.12% risk allele frequency), and Stargardt disease (2.07%). The majority (85%) of Qatari SGD pathogenic variants were not present in Western populations such as European American, South Asian American, and African American in New York City and European and Afro-Caribbean in Puerto Rico; and only 50% were observed in a broad collection of data across the Greater Middle East including Kuwait, Iran, and United Arab Emirates. This study demonstrates the feasibility of developing accurate screening tools to identify SGD risk variants in understudied populations, and the need for ancestry-specific SGD screening tools.
Highlights
A major goal of precision medicine is to optimize medical care for subgroups of patients based on genetic and/or molecular profiling[1]
The Qatari Genome Knowledgebase of single gene coding sequence pathogenic and potentially pathogenic variants was based on sequence data from 8416 Qataris, including 6218 wholegenome sequence of Qataris recruited by the Qatar BioBank (QBB)[22,23] and sequenced by the Qatar Genome Program (QGP)[24,25, 180] whole-genome sequences[12,26] and 1297 exome sequences[11] of Qataris recruited by Weill Cornell Medicine Qatar and sequenced by Illumina, Beijing Genomics Institute (BGI) or the New York Genome Center (NYGC), and 721 clinical reports from
After filtering to remove variants observed in multiple cohorts, the analysis yielded 104,473,390 total variants in 20,069 genes in the Qatari population, including 87,813,560 single nucleotide variants (SNV) and 16,659,829 indels (Table 1); below we refer to this dataset as the Qatar Genome Knowlegebase (QGK)
Summary
A major goal of precision medicine is to optimize medical care for subgroups of patients based on genetic and/or molecular profiling[1]. A challenge in widespread adaptation of genetic profiling is the genome variability among different population groups[2]. One example is the identification of pathogenic variants in (Mendelian) single gene disorders (SGDs). While the same genes are responsible, there is considerable variability across populations in the specific causative pathogenic variants[3]. While all pathogenic variants causing cystic fibrosis affect the CFTR gene, the common pathogenic variant observed in Puerto Rico[4] is different from the variant observed in Qatar[5] and both are different from the pathogenic variants common in European populations[6]. A recent analysis of ClinVar, the main NCBI database of pathogenic variants causative of SGDs, shows a significant bias towards pathogenic variants observed in European ancestry individuals[2]. As is the case for Hispanics, Blacks, and other non-
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