BACKGROUND
:
Reporting clinically actionable incidental
genetic findings in the course of clinical exome testing is
recommended by the American College of Medical Genet-
ics and Genomics (ACMG). However, the performance of
clinical exome methods for reporting small subsets of genes
has not been previously reported.
METHODS
:
In this study, 57 exome data sets performed as
clinical (n
!
12) or research (n
!
45) tests were retrospec-
tively analyzed. Exome sequencing data was examined for
adequacy in the detection of potentially pathogenic variant
locations in the 56 genes described in the ACMG incidental
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 vari-
ant 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 ex-
ome results
