Mapping the genetic landscape of treatable inherited metabolic disorders in a large Middle Eastern biobank.

BACKGROUND: To date, approximately 1,400 inherited metabolic disorders (IMDs) have been described, some of which are treatable. It is estimated that 2-3% of live births worldwide are affected by treatable IMDs. Roughly 80% of IMDs are autosomal recessive, leading to a potentially higher incidence in regions with high consanguinity. METHODOLOGY: The study utilized genome sequencing (GS) data from 14,060 adult Qatari participants who were recruited by the Qatar Biobank (QBB) and sequenced by the Qatar Genome Program (QGP). The GS data was analysed for 125 nuclear genes known to be associated with 115 treatable IMDs. RESULTS: Our study identified 253 pathogenic/likely pathogenic SNVs associated with 69 treatable IMDs, including 211 known and 42 novel predicted loss-of-function variants. We estimated that approximately 1 in 13 unrelated individuals (8%) carry a heterozygous pathogenic variant for at least one of 46 treatable IMDs. Notably, phenylketonuria/hyperphenylalaninemia and homocystinuria had among the highest carrier frequencies (1 in 68 and 1 in 85, respectively). CONCLUSION: Population-based studies of treatable IMDs, particularly in globally under-studied populations, can identify high-frequency alleles segregating in the community and inform public health policies, including carrier and newborn screening.

Qatar genome: Insights on genomics from the Middle East.

Despite recent biomedical breakthroughs and large genomic studies growing momentum, the Middle Eastern population, home to over 400 million people, is underrepresented in the human genome variation databases. Here we describe insights from Phase 1 of the Qatar Genome Program with whole genome sequenced 6047 individuals from Qatar. We identified more than 88 million variants of which 24 million are novel and 23 million are singletons. Consistent with the high consanguinity and founder effects in the region, we found that several rare deleterious variants were more common in the Qatari population while others seem to provide protection against diseases and have shaped the genetic architecture of adaptive phenotypes. These results highlight the value of our data as a resource to advance genetic studies in the Arab and neighboring Middle Eastern populations and will significantly boost the current efforts to improve our understanding of global patterns of human variations, human history, and genetic contributions to health and diseases in diverse populations.