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

Volume 52 Issue 12

Dec. 2025

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Article Navigation > Journal of Genetics and Genomics > 2025 > 52(12): 1537-1548

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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

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:

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).

Received Date: 2025-01-12
Accepted Date: 2025-03-26
Rev Recd Date: 2025-03-25
Publish Date: 2025-12-31

Abstract

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,
- Variant interpretation,
- Pathogenicity classification

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References

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