Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers

Genet Med. 2018 Aug;20(8):855-866. doi: 10.1038/gim.2017.192. Epub 2017 Nov 16.


Purpose: As massively parallel sequencing is increasingly being used for clinical decision making, it has become critical to understand parameters that affect sequencing quality and to establish methods for measuring and reporting clinical sequencing standards. In this report, we propose a definition for reduced coverage regions and describe a set of standards for variant calling in clinical sequencing applications.

Methods: To enable sequencing centers to assess the regions of poor sequencing quality in their own data, we optimized and used a tool (ExCID) to identify reduced coverage loci within genes or regions of particular interest. We used this framework to examine sequencing data from 500 patients generated in 10 projects at sequencing centers in the National Human Genome Research Institute/National Cancer Institute Clinical Sequencing Exploratory Research Consortium.

Results: This approach identified reduced coverage regions in clinically relevant genes, including known clinically relevant loci that were uniquely missed at individual centers, in multiple centers, and in all centers.

Conclusion: This report provides a process road map for clinical sequencing centers looking to perform similar analyses on their data.

Keywords: clinical sequencing; exome; genome; sequencing standards.

Publication types

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

MeSH terms

  • Base Sequence
  • Chromosome Mapping
  • Exome
  • Exome Sequencing / methods*
  • Genome, Human
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Sequence Analysis, DNA / methods*
  • Sequence Analysis, DNA / standards
  • Software
  • Whole Genome Sequencing / methods*