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Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.

ABSTRACT: With exome/genome sequencing (ES/GS) integrated into the practice of medicine, there is some potential for reporting incidental/secondary findings (IFs/SFs). The issue of IFs/SFs has been studied extensively over the last 4 years. In order to evaluate their implications in care organisation, we retrospectively evaluated, in a cohort of 700 consecutive probands, the frequency and burden of introducing the search for variants in a maximum list of 244 medically actionable genes (genes that predispose carriers to a preventable or treatable disease in childhood/adulthood and genes for genetic counselling issues). We also focused on the 59 PharmGKB class IA/IB pharmacogenetic variants. We also compared the results in different gene lists. We identified variants (likely) affecting protein function in genes for care in 26 cases (3.7%) and heterozygous variants in genes for genetic counselling in 29 cases (3.8%). Mean time for the 700 patients was about 6.3 min/patient for medically actionable genes and 1.3 min/patient for genes for genetic counselling, and a mean time of 37 min/patients for the reinterpreted variants. These results would lead to all 700 pre-test counselling sessions being longer, to 55 post-test genetic consultations and to 27 secondary specialised medical evaluations. ES also detected 42/59 pharmacogenetic variants or combinations of variants in the majority of cases. An extremely low metabolizer status in genes relevant for neurodevelopmental disorders (CYP2C9 and CYP2C19) was found in 57/700 cases. This study provides information regarding the need to anticipate the implementation of genomic medicine, notably the work overload at various steps of the process.

SUBMITTER: Thauvin-Robinet C

PROVIDER: S-EPMC6777608 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.

Thauvin-Robinet Christel C Thevenon Julien J Nambot Sophie S Delanne Julian J Kuentz Paul P Bruel Ange-Line AL Chassagne Aline A Cretin Elodie E Pelissier Aurore A Peyron Chritine C Gautier Elodie E Lehalle Daphné D Jean-Marçais Nolwenn N Callier Patrick P Mosca-Boidron Anne-Laure AL Vitobello Antonio A Sorlin Arthur A Tran Mau-Them Frédéric F Philippe Christophe C Vabres Pierre P Demougeot Laurent L Poé Charlotte C Jouan Thibaud T Chevarin Martin M Lefebvre Mathilde M Bardou Marc M Tisserant Emilie E Luu Maxime M Binquet Christine C Deleuze Jean-François JF Verstuyft Céline C Duffourd Yannis Y Faivre Laurence L

European journal of human genetics : EJHG 20190424 8

With exome/genome sequencing (ES/GS) integrated into the practice of medicine, there is some potential for reporting incidental/secondary findings (IFs/SFs). The issue of IFs/SFs has been studied extensively over the last 4 years. In order to evaluate their implications in care organisation, we retrospectively evaluated, in a cohort of 700 consecutive probands, the frequency and burden of introducing the search for variants in a maximum list of 244 medically actionable genes (genes that predispo ...[more]

PMID: 31019283

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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

Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.

Publications

Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.

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