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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


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.

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This work was supported by grants from Dijon University Hospital, the Regional Council of Burgundy Franche-Comté through the Plan d’Actions Régional pour l’Innovation (PARI 2016) and the European Union through the PO FEDER-FSE Bourgogne 2014/2020 programmes and the FEDER 2016. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would also like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

Author contributions

CTR, JT, LF, CV, AC, EC, AP, CP, YD, MB, ML and CB designed the study. SN, JD, PK, ALB, EG, DL, NJM, PC, AMB, AV, AS, FTNM, CP, PV, LD and ML interpreted the exome data. CP, FTMT, JFD, CP, TJ and MC performed the molecular laboratory work. YD and ET performed the bioinformatics analysis. All the authors contributed to the writing and review of the paper.

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Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Christel Thauvin-Robinet or Laurence Faivre.

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