Clinically actionable incidental and secondary parental genomic findings after proband exome sequencing: yield and dilemmas

ABSTRACT

Purpose Exome sequencing (ES) could detect disease-causing variants 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 disease-causing variant databases, and protein-truncating effect. Results In 14/420 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 22/840 individuals (2.6%), including 15 variants (seven founder variants) in cancer-predisposing genes and four in cardiac disease-related genes. IFs were found in three 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 already born and medico-legal aspects. Conclusion Active search for RRFs, IFs and SFs yields a high rate of findings that 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 active search can be broadly adopted in clinical genomic data analysis.