Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas
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 incidenta...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Genetics in Medicine Open |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949774423008221 |
| _version_ | 1797341888599031808 |
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| author | Lina Basel-Salmon Noa Ruhrman-Shahar Naama Orenstein Michal Levy Gabriel A. Lidzbarsky Nurit A. Batzir Marina Lifshitc-Kalis Sarit Farage-Barhom Gali Abel Mayra Petasny Dana Brabbing-Goldstein Avi Fellner Lily Bazak |
| author_facet | Lina Basel-Salmon Noa Ruhrman-Shahar Naama Orenstein Michal Levy Gabriel A. Lidzbarsky Nurit A. Batzir Marina Lifshitc-Kalis Sarit Farage-Barhom Gali Abel Mayra Petasny Dana Brabbing-Goldstein Avi Fellner Lily Bazak |
| author_sort | Lina Basel-Salmon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T10:25:29Z |
| format | Article |
| id | doaj.art-3c9f3c0169a74db9bf2377fbbc142be6 |
| institution | Directory Open Access Journal |
| issn | 2949-7744 |
| language | English |
| last_indexed | 2024-03-08T10:25:29Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj.art-3c9f3c0169a74db9bf2377fbbc142be62024-01-27T07:13:28ZengElsevierGenetics in Medicine Open2949-77442023-01-0111100813Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmasLina Basel-Salmon0Noa Ruhrman-Shahar1Naama Orenstein2Michal Levy3Gabriel A. Lidzbarsky4Nurit A. Batzir5Marina Lifshitc-Kalis6Sarit Farage-Barhom7Gali Abel8Mayra Petasny9Dana Brabbing-Goldstein10Avi Fellner11Lily Bazak12The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel; Pediatric Genetics Unit, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel; Felsenstein Medical Research Center, Tel Aviv University, Tel-Aviv, Israel; Correspondence and requests for materials should be addressed to Lina Basel-Salmon, Rabin Medical Center, Beilinson Campus, Jabotinski st. 39, Petah Tikva, 49100, Israel.The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelPediatric Genetics Unit, Schneider Children’s Medical Center of Israel, Petah Tikva, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelPediatric Genetics Unit, Schneider Children’s Medical Center of Israel, Petah Tikva, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelPediatric Genetics Unit, Schneider Children’s Medical Center of Israel, Petah Tikva, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelThe Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, IsraelPurpose: 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.http://www.sciencedirect.com/science/article/pii/S2949774423008221Exome sequencingIncidental findingsMedically actionable findingsReproduction related findingsSecondary findings |
| spellingShingle | Lina Basel-Salmon Noa Ruhrman-Shahar Naama Orenstein Michal Levy Gabriel A. Lidzbarsky Nurit A. Batzir Marina Lifshitc-Kalis Sarit Farage-Barhom Gali Abel Mayra Petasny Dana Brabbing-Goldstein Avi Fellner Lily Bazak Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas Genetics in Medicine Open Exome sequencing Incidental findings Medically actionable findings Reproduction related findings Secondary findings |
| title | Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas |
| title_full | Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas |
| title_fullStr | Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas |
| title_full_unstemmed | Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas |
| title_short | Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: Yield and dilemmas |
| title_sort | clinically actionable incidental and secondary parental genomic findings after proband exome sequencing yield and dilemmas |
| topic | Exome sequencing Incidental findings Medically actionable findings Reproduction related findings Secondary findings |
| url | http://www.sciencedirect.com/science/article/pii/S2949774423008221 |
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