Prevalence of GJB2 (Connexin-26) and GJB6 (Connexin-30) Mutations in a Cohort of 300 Brazilian Hearing-Impaired Individuals: Implications for Diagnosis and Genetic Counseling
Prevalence of GJB2 (Connexin-26) and GJB6 (Connexin-30) Mutations in a Cohort of 300 Brazilian Hearing-Impaired Individuals: Implications for Diagnosis and Genetic Counseling
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DOI：
10.1097/aud.0b013e31819144ad
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发表时间：
2009-02-01
期刊：
影响因子：
3.7
通讯作者：
Mingroni-Netto, Regina Celia
中科院分区：
文献类型：
--
作者：
Batissoco, Ana Carla;Abreu-Silva, Ronaldo Serafim;Mingroni-Netto, Regina Celia
目的：遗传性非综合征性耳聋是一种常染色体隐性遗传疾病，约80%的病例，GJB 2基因的点突变（连接蛋白26）和GJB 6基因中的两个缺失（connexin 30），del（GJB 6-D13 S1830）和del（GJB 6-D13 S1854），据报道占隐性耳聋的50%，为了确定巴西人群中GJB 2突变和GJB 6缺失的频率，我们筛选了300名不受已知耳聋相关综合征影响的听力障碍无关个体。我们首先通过特异性技术筛选了GJB 2基因中最常见的突变c.35delG和c.167delT，以及GJB 6基因中的del（GJB 6-D13 S1830）和del（GJB 6-D13 S1854）。通过测序验证检测到的c.35delG和c.167delT突变。结果：41例（13.7%）患者存在GJB 2和GJB 6基因的致病性突变，80.5%（33/41）的患者存在GJB 2和GJB 6基因的纯合或复合杂合突变，可解释其听力缺陷。GJB 2基因中的c.35delG是最常见的突变（37/300; 12.4%），在23%的家族性和6.2%的散发病例中检测到。第二个最常见的突变（1%; 3/300）是del（GJB 6-D13 S1830），总是发现与c.35delG突变相关。在GJB 2基因中发现了19种不同的序列变异。除c.35delG突变外，还检测到9种已知的致病性突变：0.67delT、p.Trp24X、p.Val37lle、c.176_191del16、c.235delC、p.Leu90Pro、p.Arg127His、c.509insA和p.Arg184Pro。15C>T、p.Val27lle、p.Met34hr、p.Ala40Ala和p.Gly160Ser。发现了两个先前报道的致病性未知的突变（p.Lys168Arg和c.684C>A），以及两个新的取代，p.Leu81Val（c.G241C）和p.Met195Val（c.A583G），两者都在杂合中，而另一个等位基因中没有伴随突变。没有这后四种变体的不确定状态是目前在一个样本中的100听力controls.Conclusions：本研究表明，GJB 2基因和del（GJB 6 D13 S1830）的突变是听力障碍的重要原因，在巴西，从而证明他们的筛选在常规的基础。我们样本中变异的多样性反映了巴西人口的种族异质性。
Objective: Hereditary nonsyndromic deafness is an autosomal recessive condition in about 80% of cases, and point mutations in the GJB2 gene (connexin 26) and two deletions in the GJB6 gene (connexin 30), del(GJB6-D13S1830) and del(GJB6-D13S1854), are reported to account for 50% of recessive deafness, Aiming at establishing the frequencies of GJB2 mutations and GJB6 deletions in the Brazilian population, we screened 300 unrelated individuals with hearing impairment, who were not affected by known deafness related syndromes.Methods: We firstly screened the most frequently reported mutations, c.35delG and c.167delT in the GJB2 gene, and del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene, through specific techniques. The detected c.35delG and c.167delT mutations were validated by sequencing. Other mutations in the GJB2 gene were screened by single-strand conformation polymorphism and the coding region was sequenced when abnormal patterns were found.Results: Pathogenic mutations in GJB2 and GJB6 genes were detected in 41 individuals (13.7%), and 80.5% (33/41) presented these mutations in homozygosis or compound heterozygosis, thus explaining their hearing defect. The c.35delG in the GJB2 gene was the most frequent mutation (37/300; 12.4%), detected in 23% familial and 6.2% the sporadic cases. The second most frequent mutation (1%; 3/300) was the del(GJB6- D13S1830), always found associated with the c.35delG mutation. Nineteen different sequence variations were found in the GJB2 gene. In addition to the c.35delG mutation, nine known pathogenic alterations were detected 0 67delT, p.Trp24X, p.Val37lle, c.176_191del16, c.235delC, p.Leu90Pro, p.Arg127His, c.509insA, and p.Arg184Pro, Five substitutions had been previously considered benign polymorphisms: c.-15C>T, p.Val27lle, p.Met34hr, p.Ala40Ala, and p.Gly160Ser. Two previously reported Mutations of unknown pathogenicity were found (p.Lys168Arg, and c.684C>A), and two novel substitutions, p.Leu81Val (c.G241C) and p.Met195Val (c.A583G), both in heterozygosis without an accompanying mutation in the other allele. None of these latter four variants of undefined status was present in a sample of 100 hearing controls.Conclusions: The present study demonstrates that Mutations in the GJB2 gene and del(GJB6 D13S1830) are important causes of hearing impairment in Brazil, thus justifying their screening in a routine basis. The diversity of variants in our sample reflects the ethnic heterogeneity of the Brazilian population.