Dataset Information

Actionable Exomic Secondary Findings in 280 Lebanese Participants.

ABSTRACT: The expanded use of NGS tests in genetic diagnosis enables the massive generation of data related to each individual, among which some findings are of medical value. Over the last three and a half years, 280 unrelated Lebanese patients, presenting a wide spectrum of genetic disorders were referred to our center for genetic evaluation by WES. Molecular diagnosis was established in 56% of the cases, as was previously reported. The current study evaluates secondary findings in these patients in 59 genes, linked to conditions mostly responsive to medical interventions, as per the ACMG guidelines. Our analysis allowed us to detect 19 pathogenic/likely pathogenic variants in 24 individuals from our cohort. Dominant actionable variants were found in 17 individuals representing 6% of the studied population. Genes associated with dominant cardiac diseases were the most frequently mutated: variants were found in 2.1% of our cohort. Genetic predisposition to cancer syndromes was observed in 1.07% of the cases. In parallel to dominant disease alleles, our analysis identified a recessive pathogenic disease allele in 2.5% of the individuals included in this study. Of interest, some variants were detected in different patients from our cohort thus urging the study of their prevalence in our population and the implementation, when needed, of specific genetic testing in the neonatal screening panel. In conclusion, here we report the first study estimating the actionable pathogenic variant load in the Lebanese population. Communicating current findings to the patients will enable them to benefit from a multi-disciplinary approach. Furthermore, tailoring the ACMG guidelines to the population is suggested, especially in highly consanguineous populations where the information related to recessive alleles might be highly beneficial to patients and their families.

SUBMITTER: Jalkh N

PROVIDER: S-EPMC7083077 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Actionable Exomic Secondary Findings in 280 Lebanese Participants.

Jalkh Nadine N Mehawej Cybel C Chouery Eliane E

Frontiers in genetics 20200313

The expanded use of NGS tests in genetic diagnosis enables the massive generation of data related to each individual, among which some findings are of medical value. Over the last three and a half years, 280 unrelated Lebanese patients, presenting a wide spectrum of genetic disorders were referred to our center for genetic evaluation by WES. Molecular diagnosis was established in 56% of the cases, as was previously reported. The current study evaluates secondary findings in these patients in 59 ...[more]

PMID: 32231684

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Project description:The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.

Dataset Information

Actionable Exomic Secondary Findings in 280 Lebanese Participants.

Publications

Actionable Exomic Secondary Findings in 280 Lebanese Participants.

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