Basel-Salmon Lina, Ruhrman-Shahar Noa, Orenstein Naama, Levy Michal, Lidzbarsky Gabriel A, Batzir Nurit A, Lifshitc-Kalis Marina, Farage-Barhom Sarit, Abel Gali, Petasny Mayra, Brabbing-Goldstein Dana, Fellner Avi, Bazak Lily
The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel.
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
Genet Med Open. 2023 Apr 29;1(1):100813. doi: 10.1016/j.gimo.2023.100813. eCollection 2023.
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.
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.
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.
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.
外显子组测序（ES）能够检测出与检测指征无关的致病变异，包括可能对考虑受孕/生育的患者产生影响的结果（生殖相关结果[RRFs]）、特意搜索的次要结果（SFs）以及偶然发现（IFs）。我们旨在研究840名接受临床三联体ES检测的先证者父母中临床可操作结果的检出率，并呈现咨询困境。
作为ES数据分析的一部分，在父母中积极搜索RRFs/IFs/SFs。通过频率、遗传模式、ClinVar分类、当地致病变异数据库中的存在情况以及蛋白质截短效应来筛选变异。
在420个家庭中的14个（3.3%）检测到了15个RRFs。在23.3%的近亲配偶和1.8%的非近亲配偶中发现了常染色体隐性疾病的共同父母杂合状态。在840名个体中的22名（2.6%）发现了SFs，包括癌症易感基因中的15个变异（7个奠基者变异）和心脏病相关基因中的4个变异。在3名无报告症状的个体中发现了IFs。总体而言，9.3%的家庭中检测到了具有潜在医学重要性的变异。与是否报告变异相关的挑战包括未报告的父母表型、症状前检测、可变的疾病表达、对已出生子女的潜在医学影响以及法医学方面。
积极搜索RRFs、IFs和SFs可产生较高的发现率，这可能有助于对接受ES检测的先证者父母进行个体化医疗。在临床基因组数据分析中广泛采用这种积极搜索之前，应考虑采用一种结构化方法来克服与报告这些发现相关的挑战。
