Analysis of 14,392 whole genomes reveals 3.5% of Qataris carry medically actionable variants

Abstract

Arabic populations are underrepresented in large genome projects; therefore, the frequency of clinically actionable variants among Arabs is largely unknown. Here, we investigated genetic variation in 14,392 whole genomes from the Qatar Genome Program (QGP) across the list of 78 actionable genes (v3.1) determined by the American College of Medical Genetics and Genomics (ACMG). Variants were categorized into one of the following groups: (1) Pathogenic (P), (2) Likely pathogenic (LP), and (3) Rare variants of uncertain significance with evidence of pathogenicity. For the classification, we used variant databases, effect predictors, and the disease-relevant phenotypes available for the cohort. Data on cardiovascular disease, cancer, and hypercholesterolemia allowed us to assess the disease-relevant phenotype association of rare missense variants. We identified 248 distinct variants in 50 ACMG genes that fulfilled our criteria to be included in one of the three groups affecting 1036 genotype-positive participants of the QGP cohort. The most frequent variants were in TTN, followed by RYR1 and ATP7B. The prevalence of reportable secondary findings was 3.5%. A further 46 heterozygous variants in six genes with an autosomal recessive mode of inheritance were detected in 200 individuals, accounting for an additional 1.4%. Altogether, they affect 5% of the population. Due to the high consanguinity rate in the QGP cohort (28% in spouses and 60% in parents), P and LP variants both in genes with dominant and recessive inheritance are important for developing better treatment options and preventive strategies in Qatar and the Arabic population of the Middle East.

Fig. 1. Flow chart of the pipeline for actionable variant identification in 78 ACMG genes.

WGS whole genome sequencing, QGP Qatar Genome Program, B benign, LB likely benign, P pathogenic, LP likely pathogenic, DM disease-causing, HGMD Human Gene Mutation Database, LOF loss of function, VUS rare variants of uncertain significance with evidence of pathogenicity, AC allele count, MAF minor allele frequency, CVD cardiovascular diseases, V variants, GPPs genotype-positive participants.

Fig. 2. Variants and participants in the Qatar genome program reported lists.

A Total number of genotype positive participants carrying variants in the QGP across the three lists. B Total number of variants in the QGP across the three lists based on 78 ACMG genes. GPP genotype positive participants, FH familial hypercholesterolemia.

Fig. 3. The distribution of actionable variants based on ACMG disease categories.

A Distribution of genotype positive participants carrying actionable variants based on 78 ACMG gene-associated phenotypes. B Distribution of actionable variants among 78 ACMG gene- associated phenotypes. C Frequency of genotype positive participants carrying actionable variants based on 78 ACMG gene-associated phenotypes. GPP genotype positive participants, FH familial hypercholesterolemia.