The implications of familial incidental findings from exome sequencing: The NIH Undiagnosed Diseases Program experience

PURPOSE: Using exome sequence data from 159 families participating in the NIH Undiagnosed Diseases Program, we evaluated the number and inheritance of reportable incidental sequence variants. METHODS: Following the ACMG recommendations for reporting of incidental next generation sequencing findings, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data. RESULTS: We identified 14 independent reportable variants in 159 (8.8%) families. For 9 families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (9 minor children and 4 adult children). The remaining 5 variants occurred in adults for whom parental sequences were unavailable. CONCLUSION: Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the ACMG recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling of the family.