Clinical exome performance for reporting secondary genetic findings

Jason Y. Park, Peter Clark, Eric Londin, Marialuisa Sponziello, Larry J. Kricka, Paolo Fortina

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Methods: In this study, 57 exome data sets performed as clinical (n = 12) or research (n = 45) tests were retrospectively analyzed. Exome sequencing data was examined for adequacy in the detection of potentially pathogenic variant locations in the 56 genes described in theACMGincidental findings recommendation. All exons of the 56 genes were examined for adequacy of sequencing coverage. In addition, nucleotide positions annotated in HGMD (Human Gene Mutation Database) were examined.

Results: The 56 ACMG genes have 18336 nucleotide variants annotated in HGMD. None of the 57 exome data sets possessed a HGMD variant. The clinical exome test had inadequate coverage for >50% of HGMD variant locations in 7 genes. Six exons from 6 different genes had consistent failure across all 3 test methods; these exons had high GC content (76%-84%).

Conclusions: The use of clinical exome sequencing for the interpretation and reporting of subsets of genes requires recognition of the substantial possibility of inadequate depth and breadth of sequencing coverage at clinically relevant locations. Inadequate depth of coverage may contribute to false-negative clinical exome results.

Background: Reporting clinically actionable incidental genetic findings in the course of clinical exome testing is recommended by the American College of Medical Genetics and Genomics (ACMG). However, the performance of clinical exome methods for reporting small subsets of genes has not been previously reported.

Original languageEnglish (US)
Pages (from-to)213-220
Number of pages8
JournalClinical chemistry
Issue number1
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • General Medicine


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