Analysis of incidental findings in Qatar genome participants reveals novel functional variants in LMNA and DSP.

In order to report clinically actionable incidental findings in genetic testing, the American College of Medical Genetics and Genomics (ACMG) recommended the evaluation of variants in 59 genes associated with highly penetrant mutations. However, there is a lack of epidemiological data on medically actionable rare variants in these genes in Arab populations. We used whole genome sequencing data from 6045 participants from the Qatar Genome Programme and integrated it with phenotypic data collected by the Qatar Biobank. We identified novel putative pathogenic variants in the 59 ACMG genes by filtering previously unrecorded variants based on computational prediction of pathogenicity, variant rarity and segregation evidence. We assessed the phenotypic associations of candidate variants in genes linked to cardiovascular diseases. Finally, we used a zebrafish knockdown and synthetic human mRNA co-injection assay to functionally characterize two of these novel variants. We assessed the zebrafish cardiac function in terms of heart rate, rhythm and hemodynamics, as well as the heart structure. We identified 52 492 novel variants, which have not been reported in global and disease-specific databases. A total of 74 novel variants were selected with potentially pathogenic effect. We prioritized two novel cardiovascular variants, DSP c.1841A > G (p.Asp614Gly) and LMNA c.326 T > G (p.Val109Gly) for functional characterization. Our results showed that both variants resulted in abnormal zebrafish heart rate, rhythm and structure. This study highlights medically actionable variants that are specific to the Middle Eastern Qatari population.

Actionable genomic variants in 6045 participants from the Qatar Genome Program.

In a clinical setting, DNA sequencing can uncover findings unrelated to the purpose of genetic evaluation. The American College of Medical Genetics and Genomics (ACMG) recommends the evaluation and reporting of 59 genes from clinic genomic sequencing. While the prevalence of secondary findings is available from large population studies, these data lack Arab and other Middle Eastern populations. The Qatar Genome Program (QGP) generates whole-genome sequencing (WGS) data and combines it with phenotypic information to create a comprehensive database for studying the Qatari and wider Arab and Middle Eastern populations at the molecular level. This study identified and analyzed medically actionable variants in the 59 ACMG genes using WGS data from 6045 QGP participants. Our results identified a total of 60 pathogenic and likely pathogenic variants in 25 ACMG genes in 141 unique individuals. Overall, 2.3% of the QGP sequenced participants carried a pathogenic or likely pathogenic variant in one of the 59 ACMG genes. We evaluated the QGP phenotype-genotype association of additional nonpathogenic ACMG variants. These variants were found in patients from the Hamad Medical Corporation or reported incidental findings data in Qatar. We found a significant phenotype association for two variants, c.313+3A>C in LDLR, and c.58C>T (p.Gln20*) in the TPM1.

Frequency and management of medically actionable incidental findings from genome and exome sequencing data: a systematic review.

The application of whole genome/exome sequencing technologies in clinical genetics and research has resulted in the discovery of incidental findings unrelated to the primary purpose of genetic testing. The American College of Medical Genetics and Genomics published guidelines for reporting pathogenic and likely pathogenic variants that are deemed to be medically actionable, which allowed us to learn about the epidemiology of incidental findings in different populations. However, consensus guidelines for variant reporting and classification are still lacking. We conducted a systematic literature review of incidental findings in whole genome/exome sequencing studies to obtain a comprehensive understanding of variable reporting and classification methods for variants that are deemed to be medically actionable across different populations. The review highlights the elements that demand further consideration or adjustment.

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

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.