Interpretation of pathogenic variants and genetic counselling for mitochondrial hearing loss
10.3760/cma.j.cn115330-20230831-00069
- VernacularTitle:携带线粒体DNA致病突变家庭的聋病遗传咨询特征分析
- Author:
Jing GUAN
1
;
Jin LI
;
Xiaonan WU
;
Yun GAO
;
Hongyang WANG
;
Qiuju WANG
Author Information
1. 解放军总医院第六医学中心耳鼻咽喉头颈外科医学部 国家耳鼻咽喉疾病临床医学研究中心，北京 100853
- Keywords:
DNA, mitochondrial;
Mitochondrial hearing loss;
Genetic counseling;
MT-RNR1;
MT-TS1;
MT-TL1
- From:
Chinese Journal of Otorhinolaryngology Head and Neck Surgery
2023;58(11):1077-1085
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To analyze the genetic counseling characteristics and interpretation of pathogenic variants for mitochondrial hearing loss.Methods:We analyzed a total of 513 unrelated families from Chinese Deafness Genome Project (CDGP), in which previous gene testing had found no pathogenic mutations with hearing loss (HL) related to the nuclear genes. We used targeted testing and complete mtDNA sequencing for the families′ available members.Results:Among the first individuals of the families to be tested, 20 cases (16 probands and 4 normal hearing consultants) were discovered with variants in mtDNA, including m.1095T>C, m.1310C>T, m.1494C>T and m.1555A>G in MT-RNR1, m.7445A>G, m.7505T>C, m.7510T>C and m.7511T>C in MT-TS1, and m.3243A>G in MT-TL1. We identified MT-RNR1 and MT-TS1 variants occurred as homoplasmic changes, while MT-TL1 variants occurred as heteroplasmic changes. Most mitochondrial hearing loss were characterized by slope or flat moderate to profound sensorineural HL. HL associated with the mtDNA pathogenic variant was variable onset age, severity and audiometric configuration. The penetrance for HL in individuals with the m.1095T>C variant might be low. Progression in the severity of HL was caused by the m.7445A>G pathogenic variant and the patients with m.7505T>C had cookie bite HL. MT-TL1 m.3243A>G was a common spot for pathogenic variants associated with nonsyndromic HL as well as syndromic HL with diabetes mellitus. Conclusions:Individuals with the mtDNA variants and their maternal relatives have a higher risk of HL and phenotypic heterogeneity in the age of onset, progression, and level of HL. The medical history should include review of any audiological testing of the probands and their family members on a maternal mtDNA background. The process of genetic evaluation needs rule out nuclear gene mutations and analyzes the genetic load of mitochondrial pathogenic variants in the probands or consultants. In these cases, we rely on clinical and genetic evaluation molecular analysis to appropriately counsel families for whom an exact cause of HL and to help them make informed medical decisions.
