EVALUATION OF MEDICALLY ACTIONABLE GENES IN 6,045 WHOLE GENOME SEQUENCING DATA FROM THE QATAR GENOME PROJECT

Abstract

Introduction: The American College of Medical Genetics (ACMG) identified 59 genes in which incidental findings of medically actionable pathogenic variants is recommended to be reported. The prevalence of these variants from Arab and other Middle Eastern populations is still lacking. The Qatar Genome Program (QGP), which is a large, population-based whole genome sequencing project with comprehensive phenotypic information, allowed us to identify and analyse the medically actionable variants in these genes in the Qatari population. Materials and Methods: We used data from 6,045 whole genomes from the QGP and integrated it with phenotypic data collected by the Qatar Biobank. We identified known pathogenic and likely pathogenic variants based on ClinVar and the Human Gene Mutation Database professional entries. Additionally, we identified novel variants, assessed their phenotypic associations, and functionally characterized two novel variants in zebrafish. Results: We identified a total of 60 pathogenic and likely pathogenic variants in 25 ACMG genes in 141 individuals. Overall, 2.3% of the QGP-sequenced participants carried a pathogenic or likely pathogenic variant in one of the 59 ACMG genes. We found 74 novel, potentially pathogenic variants. We prioritized two novel candidate cardiovascular variants, DSP c.1841A>G (p.Asp614Gly) and LMNA c.326T>G (p.Val109Gly) for functional characterization. Our results showed that both variants resulted in abnormal zebrafish heart structure, heart rate and rhythm. Conclusion: The prevalence of known medically actionable variants in the Qatari population is slightly higher than in other populations. There is a comparable number of predicted pathogenic novel variants. We confirmed the pathogenicity of two novel variants in zebrafish.

Date of Award	2021
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences