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

Genet Med. 2014 Oct;16(10):741-50. doi: 10.1038/gim.2014.29. Epub 2014 May 1.


Purpose: Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants.

Methods: Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, 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 nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five 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 American College of Medical Genetics and Genomics 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 for the family.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Cohort Studies
  • Exome / genetics*
  • Family Health
  • Female
  • Genetic Counseling
  • Genetic Diseases, Inborn / diagnosis
  • Genetic Diseases, Inborn / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation*
  • Genome, Human / genetics
  • Humans
  • Incidental Findings
  • Male
  • Metabolism, Inborn Errors / diagnosis
  • Metabolism, Inborn Errors / genetics
  • Middle Aged
  • National Institutes of Health (U.S.)
  • Sequence Analysis, DNA / methods*
  • United States
  • Young Adult