Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic).
Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic).
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DOI：
10.1371/journal.pone.0156300
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Fedorova SA
中科院分区：
文献类型：
--
作者：
Barashkov NA;Pshennikova VG;Posukh OL;Teryutin FM;Solovyev AV;Klarov LA;Romanov GP;Gotovtsev NN;Kozhevnikov AA;Kirillina EV;Sidorova OG;Vasilyevа LM;Fedotova EE;Morozov IV;Bondar AA;Solovyevа NA;Kononova SK;Rafailov AM;Sazonov NN;Alekseev AN;Tomsky MI;Dzhemileva LU;Khusnutdinova EK;Fedorova SA
已知编码连接蛋白26的GJB 2基因中的致病性变体是听力损伤（HI）的主要原因。在GJB 2基因中已经鉴定出超过300种等位基因变体。GJB 2基因的谱和等位基因频率在全球不同种族之间存在显着差异。到目前为止，位于俄罗斯亚北极地区的萨哈共和国（雅库特）的GJB 2基因外显子1、外显子2和侧翼内含子区的致病性变异的谱和频率尚未得到彻底描述。在393例HI患者（雅库特人-296例，俄罗斯人-51例，混合和其他种族-46例）和雅库特人（n = 107）和俄罗斯人（n = 80）人群的187名正常听力个体中进行了GJB 2基因非编码区和编码区的完整测序。在总样本（n = 580），我们发现12个等位基因变异的GJB 2基因，其中8个是隐性致病变异。在393例患者中，192例（48.85%）发现GJB 2基因的10种双等位基因隐性致病变异型（纯合或复合杂合状态）。我们发现雅库特患者中最常见的GJB 2致病性变体是c. 23+1G>A（51.82%），其次为c.109G>A（2.37%），其次为c.35delG（1.64%）。致病性变异体c. 35 delG（22.34%），c. 23+1G>A（5.31%）和c.313_326del14（2.12%）在俄罗斯患者中最常见。C的载波频率雅库特对照组23+1G>A和с.109G>A致病变异分别为10.20%和2.80%。在俄罗斯对照组中，с.35delG和c.101T>C的携带者频率相同（2.5%）。我们发现，GJB 2基因致病性变异的贡献HI在人口的萨哈共和国（48.85%）是所有以前研究的亚洲地区中最高的。我们认为，广泛积累的c。23+1G>土著雅库特人群中的致病性变异（患者中所有突变染色体的92.20%）和对照组中极高（10.20%）的携带者频率可能表明c. 23+1G>A生活在亚北极气候的携带者。
Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts—296, Russians—51, mixed and other ethnicities—46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate.