February 11, 2022  |  

Curated variation benchmarks for challenging medically relevant autosomal genes

Authors: Wagner, Justin and Olson, Nathan D. and Harris, Lindsay and McDaniel, Jennifer and Cheng, Haoyu and Fungtammasan, Arkarachai and Hwang, Yih-Chii and Gupta, Richa and Wenger, Aaron M. and Rowell, William J. and Khan, Ziad M. and Farek, Jesse and Zhu, Yiming and Pisupati, Aishwarya and Mahmoud, Medhat and Xiao, Chunlin and Yoo, Byunggil and Sahraeian, Sayed Mohammad Ebrahim and Miller, Danny E. and Jáspez, David and Lorenzo-Salazar, José M. and Muñoz-Barrera, Adrián and Rubio-Rodríguez, Luis A. and Flores, Carlos and Narzisi, Giuseppe and Evani, Uday Shanker and Clarke, Wayne E. and Lee, Joyce and Mason, Christopher E. and Lincoln, Stephen E. and Miga, Karen H. and Ebbert, Mark T. W. and Shumate, Alaina and Li, Heng and Chin, Chen-Shan and Zook, Justin M. and Sedlazeck, Fritz J.

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.

Journal: Nature Biotechnology
DOI: 10.1038/s41587-021-01158-1
Year: 2022

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