Exome variant discrepancies due to reference-genome differences.

Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE

Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.

Exome* ; Genome, Human* ; Polymorphism, Single Nucleotide*; Cohort Studies ; Genetic Diseases, Inborn/genetics ; Humans ; Reference Values

Despite release of the GRCh38 human reference genome more than seven years ago, GRCh37 remains more widely used by most research and clinical laboratories. To date, no study has quantified the impact of utilizing different reference assemblies for the identification of variants associated with rare and common diseases from large-scale exome-sequencing data. By calling variants on both the GRCh37 and GRCh38 references, we identified single-nucleotide variants (SNVs) and insertion-deletions (indels) in 1,572 exomes from participants with Mendelian diseases and their family members. We found that a total of 1.5% of SNVs and 2.0% of indels were discordant when different references were used. Notably, 76.6% of the discordant variants were clustered within discrete discordant reference patches (DISCREPs) comprising only 0.9% of loci targeted by exome sequencing. These DISCREPs were enriched for genomic elements including segmental duplications, fix patch sequences, and loci known to contain alternate haplotypes. We identified 206 genes significantly enriched for discordant variants, most of which were in DISCREPs and caused by multi-mapped reads on the reference assembly that lacked the variant call. Among these 206 genes, eight are implicated in known Mendelian diseases and 53 are associated with common phenotypes from genome-wide association studies. In addition, variant interpretations could also be influenced by the reference after lifting-over variant loci to another assembly. Overall, we identified genes and genomic loci affected by reference assembly choice, including genes associated with Mendelian disorders and complex human diseases that require careful evaluation in both research and clinical applications.
(Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

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K08 HG008986 United States HG NHGRI NIH HHS; R35 NS105078 United States NS NINDS NIH HHS; U54 HG003273 United States HG NHGRI NIH HHS; UM1 HG006542 United States HG NHGRI NIH HHS

Keywords: GRCh37; GRCh38; Human Genome Reference; clinical genome sequencing; exome sequencing; hg19

Date Created: 20210615 Date Completed: 20210831 Latest Revision: 20240923

20240923

PMC8322936

10.1016/j.ajhg.2021.05.011

34129815