Curated variation benchmarks for challenging medically relevant autosomal genes.

TitleCurated variation benchmarks for challenging medically relevant autosomal genes.
Publication TypeJournal Article
Year of Publication2022
AuthorsWagner, J, Olson, ND, Harris, L, McDaniel, J, Cheng, H, Fungtammasan, A, Hwang, Y-C, Gupta, R, Wenger, AM, Rowell, WJ, Khan, ZM, Farek, J, Zhu, Y, Pisupati, A, Mahmoud, M, Xiao, C, Yoo, B, Sahraeian, SMohammad E, Miller, DE, Jáspez, D, Lorenzo-Salazar, JM, Muñoz-Barrera, A, Rubio-Rodríguez, LA, Flores, C, Narzisi, G, Evani, UShanker, Clarke, WE, Lee, J, Mason, CE, Lincoln, SE, Miga, KH, Ebbert, MTW, Shumate, A, Li, H, Chin, C-S, Zook, JM, Sedlazeck, FJ
JournalNat Biotechnol
Date Published2022 Feb 07

The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.

Alternate JournalNat Biotechnol
PubMed ID35132260
Grant ListUM1 HG008898 / HG / NHGRI NIH HHS / United States
R01 CA249054 / CA / NCI NIH HHS / United States
R01 HG010040 / HG / NHGRI NIH HHS / United States
BOC n.º 163, 24/08/2017 / / Cabildo Insular de La Palma /
Intramural / / U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM) /
Intramural / / United States Department of Commerce | National Institute of Standards and Technology (NIST) /
U01 DA053941 / DA / NIDA NIH HHS / United States
R01 MH117406 / MH / NIMH NIH HHS / United States
R01 AI151059 / AI / NIAID NIH HHS / United States
PI20/00876 / / Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III) /