Multiple nucleotide variants in genetic diagnosis: implications from 11,467 cases of hearing loss

Fandi Ai; Jiayi Zeng; Qian Zhang; Mingjun Zhong; Meilin Chen; Yu Lu; Jing Cheng; Lei Chen; Fengxiao Bu; Huijun Yuan

doi:10.1016/j.jgg.2025.03.012

Multiple nucleotide variants in genetic diagnosis: implications from 11,467 cases of hearing loss

doi: 10.1016/j.jgg.2025.03.012

a. Department of Oto-Rhino-Laryngology, Institute of Rare Diseases, Frontiers Science Center for Disease-related Molecular Networks, West China Hospital, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610041, China;
b. The Second People's Hospital of Hunan Province (Brain Hospital of Hunan Province), Changsha, Hunan 410007, China;
c. Department of Neurology, Frontiers Science Center for Disease-related Molecular Networks, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China

基金项目:

This research was financially supported by the Key Project of the National Natural Science Foundation of China (82030030), the National Natural Science Foundation of China (82171836), the Science and Technology Department of Sichuan Province (2024NSFSC0648), and the 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC20002). We are very grateful to all the patients and families who generously participated in the CDGC study. Sincere appreciation is also extended to the National Supercomputing Center in Chengdu and the Information Center of West China Hospital for providing data analytical and storage resources, along with technical support.

详细信息

通讯作者:
Lei Chen,E-mail:leilei_25@126.com

Fengxiao Bu,E-mail:bufengxiao@wchscu.cn

Huijun Yuan,E-mail:yuanhj301@wchscu.cn

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出版历程
- 收稿日期: 2025-01-12
- 录用日期: 2025-03-26
- 修回日期: 2025-03-25
- 网络出版日期: 2025-07-11

Multiple nucleotide variants in genetic diagnosis: implications from 11,467 cases of hearing loss

Fandi Ai^a,
Jiayi Zeng^a,
Qian Zhang^a,
Mingjun Zhong^a,
Meilin Chen^b,
Yu Lu^a,
Jing Cheng^a,
Lei Chen^{c
, ,},
Fengxiao Bu^{a
, ,},
Huijun Yuan^{a
, ,}

a. Department of Oto-Rhino-Laryngology, Institute of Rare Diseases, Frontiers Science Center for Disease-related Molecular Networks, West China Hospital, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610041, China;
b. The Second People's Hospital of Hunan Province (Brain Hospital of Hunan Province), Changsha, Hunan 410007, China;
c. Department of Neurology, Frontiers Science Center for Disease-related Molecular Networks, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China

Funds:

摘要

摘要:
Multiple nucleotide variants (MNVs) are frequently misannotated as separate single-nucleotide variants (SNVs) by widely utilized variant-calling pipelines, presenting substantial challenges in genetic testing and research. The role of MNVs in genetic diagnosis remains inadequately characterized, particularly within large disease cohorts. In this study, we comprehensively investigate codon-level MNVs (cMNVs) across 157 hearing loss (HL)-related genes in 11,467 HL cases and 7258 controls from the Chinese Deafness Gene Consortium (CDGC) cohort. A total of 116 cMNVs are identified, occurring in 29.07% of HL cases. Among them, 56.03% of cMNVs exhibit functional consequences distinct from constituent SNVs. Moreover, amino acid substitutions exclusive to cMNVs cause more substantial physicochemical disruptions than those associated with SNVs. Notably, 51 cMNVs show pathogenicity classifications that diverge from at least one constituent SNV, impacting genetic interpretation in 145 cases. Pathogenicity interpretation of cMNV facilitates definitive genetic diagnoses in eight HL cases that would otherwise have been subject to misdiagnoses or missed diagnoses. These findings provide critical insights into the genomic characteristics, functional impacts, and diagnostic implications of cMNVs, underscoring their clinical significance in genetic diagnosis and emphasizing the necessity for comprehensive and accurate detection and interpretation of cMNVs in genetic testing and research.
- Multiple nucleotide variants /
- Genetic diagnosis /
- Hearing loss
Abstract:
Multiple nucleotide variants (MNVs) are frequently misannotated as separate single-nucleotide variants (SNVs) by widely utilized variant-calling pipelines, presenting substantial challenges in genetic testing and research. The role of MNVs in genetic diagnosis remains inadequately characterized, particularly within large disease cohorts. In this study, we comprehensively investigate codon-level MNVs (cMNVs) across 157 hearing loss (HL)-related genes in 11,467 HL cases and 7258 controls from the Chinese Deafness Gene Consortium (CDGC) cohort. A total of 116 cMNVs are identified, occurring in 29.07% of HL cases. Among them, 56.03% of cMNVs exhibit functional consequences distinct from constituent SNVs. Moreover, amino acid substitutions exclusive to cMNVs cause more substantial physicochemical disruptions than those associated with SNVs. Notably, 51 cMNVs show pathogenicity classifications that diverge from at least one constituent SNV, impacting genetic interpretation in 145 cases. Pathogenicity interpretation of cMNV facilitates definitive genetic diagnoses in eight HL cases that would otherwise have been subject to misdiagnoses or missed diagnoses. These findings provide critical insights into the genomic characteristics, functional impacts, and diagnostic implications of cMNVs, underscoring their clinical significance in genetic diagnosis and emphasizing the necessity for comprehensive and accurate detection and interpretation of cMNVs in genetic testing and research.
- Multiple nucleotide variants /
- Genetic diagnosis /
- Hearing loss

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Multiple nucleotide variants in genetic diagnosis: implications from 11,467 cases of hearing loss

doi: 10.1016/j.jgg.2025.03.012

通讯作者:
Lei Chen,E-mail:leilei_25@126.com

Fengxiao Bu,E-mail:bufengxiao@wchscu.cn

Huijun Yuan,E-mail:yuanhj301@wchscu.cn

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Multiple nucleotide variants in genetic diagnosis: implications from 11,467 cases of hearing loss

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Multiple nucleotide variants in genetic diagnosis: implications from 11,467 cases of hearing loss

doi: 10.1016/j.jgg.2025.03.012

通讯作者: Lei Chen,E-mail:leilei_25@126.com Fengxiao Bu,E-mail:bufengxiao@wchscu.cn Huijun Yuan,E-mail:yuanhj301@wchscu.cn

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Multiple nucleotide variants in genetic diagnosis: implications from 11,467 cases of hearing loss

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出版历程

目录

通讯作者:
Lei Chen,E-mail:leilei_25@126.com

Fengxiao Bu,E-mail:bufengxiao@wchscu.cn

Huijun Yuan,E-mail:yuanhj301@wchscu.cn