TY - JOUR
T1 - Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing
T2 - Yield and dilemmas
AU - Basel-Salmon, Lina
AU - Ruhrman-Shahar, Noa
AU - Orenstein, Naama
AU - Levy, Michal
AU - Lidzbarsky, Gabriel A.
AU - Batzir, Nurit A.
AU - Lifshitc-Kalis, Marina
AU - Farage-Barhom, Sarit
AU - Abel, Gali
AU - Petasny, Mayra
AU - Brabbing-Goldstein, Dana
AU - Fellner, Avi
AU - Bazak, Lily
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - Purpose: Exome sequencing (ES) could detect pathogenic variants that are unrelated to the test indication, including findings that may have an impact for patients considering conception/reproduction (reproduction-related findings [RRFs]), deliberately searched secondary findings (SFs), and incidental findings (IFs). We aimed to examine the detection rate of clinically actionable findings and to present counseling dilemmas in 840 parents of probands undergoing clinical trio ES testing. Methods: RRFs/IFs/SFs were actively searched for in the parents as part of ES data analysis. Variants were filtered by frequency, mode of inheritance, ClinVar classification, presence in local pathogenic variant databases, and protein-truncating effect. Results: In 14 of 420 families (3.3%), 15 RRFs were detected. Shared parental heterozygous status for autosomal recessive disorders was identified in 23.3% of consanguineous and 1.8% of nonconsanguineous couples. SFs were found in 22 of 840 individuals (2.6%), including 15 variants (7 founder variants) in cancer-predisposing genes and 4 in cardiac disease–related genes. IFs were found in 3 individuals without reported symptoms. Overall, variants of potential medical importance were detected in 9.3% of families. Challenges related to the decision whether to report variants included unreported parental phenotype, presymptomatic testing, variable disease expressivity, potential medical implications for children who are already born, and medicolegal aspects. Conclusion: Active search for RRFs, IFs, and SFs yields a high rate of findings, which may contribute to individual medical care in parents of probands undergoing ES. A structured approach to overcome the challenges associated with reporting these findings should be considered before such an active search can be broadly adopted in clinical genomic data analysis.
AB - Purpose: Exome sequencing (ES) could detect pathogenic variants that are unrelated to the test indication, including findings that may have an impact for patients considering conception/reproduction (reproduction-related findings [RRFs]), deliberately searched secondary findings (SFs), and incidental findings (IFs). We aimed to examine the detection rate of clinically actionable findings and to present counseling dilemmas in 840 parents of probands undergoing clinical trio ES testing. Methods: RRFs/IFs/SFs were actively searched for in the parents as part of ES data analysis. Variants were filtered by frequency, mode of inheritance, ClinVar classification, presence in local pathogenic variant databases, and protein-truncating effect. Results: In 14 of 420 families (3.3%), 15 RRFs were detected. Shared parental heterozygous status for autosomal recessive disorders was identified in 23.3% of consanguineous and 1.8% of nonconsanguineous couples. SFs were found in 22 of 840 individuals (2.6%), including 15 variants (7 founder variants) in cancer-predisposing genes and 4 in cardiac disease–related genes. IFs were found in 3 individuals without reported symptoms. Overall, variants of potential medical importance were detected in 9.3% of families. Challenges related to the decision whether to report variants included unreported parental phenotype, presymptomatic testing, variable disease expressivity, potential medical implications for children who are already born, and medicolegal aspects. Conclusion: Active search for RRFs, IFs, and SFs yields a high rate of findings, which may contribute to individual medical care in parents of probands undergoing ES. A structured approach to overcome the challenges associated with reporting these findings should be considered before such an active search can be broadly adopted in clinical genomic data analysis.
KW - Exome sequencing
KW - Incidental findings
KW - Medically actionable findings
KW - Reproduction related findings
KW - Secondary findings
UR - http://www.scopus.com/inward/record.url?scp=85183618831&partnerID=8YFLogxK
U2 - 10.1016/j.gimo.2023.100813
DO - 10.1016/j.gimo.2023.100813
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AN - SCOPUS:85183618831
SN - 2949-7744
VL - 1
JO - Genetics in Medicine Open
JF - Genetics in Medicine Open
IS - 1
M1 - 100813
ER -