Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness
Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness
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DOI：
10.1001/jama.281.23.2211
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发表时间：
1999-06-16
影响因子：
120.7
通讯作者：
Smith, RJH
中科院分区：
文献类型：
--
作者：
Green, GE;Scott, DA;Smith, RJH
GJB2基因突变是遗传性先天性重度至重度耳聋最常见的已知原因，这些突变的载体频率尚不清楚。目的确定美国中西部地区GJB2致聋基因突变的携带率，以及这些突变在先天性感音神经性听力损失患者中从中度到重度的患病率，并为咨询提供修订数据。设计实验室于1998年使用等位基因特异性聚合酶链反应测定、单链构象多态性分析和直接测序对听力损失先证的GJB2突变样本进行了分析。52名年龄小于19岁的受试者因听力损失或人工耳蜗植入被依次转诊到中西部三级转诊中心，这些患者有不明原因的中度至重度先天性听力损失，父母无血缘关系，以及听力损失仅限于一代的非综合征性耳聋；对560名对照新生儿进行35delG突变筛查。主要观察指标GJB2基因突变与先天性耳聋状况的关系。结果在52例先天性感音神经性听力损失的顺序先证者中，22例（42%）发现GJB2突变。41个突变等位基因中有29个突变35delG。先证者的兄弟姐妹中，纯合子和复合杂合子均有耳聋。560例对照中有14例为35delG杂合子，平均（SE）为2.5%（0.66%）。所有导致隐性耳聋的GJB2突变的携带率为3.01%（可能范围为2.54%-3.56%）。单独基于35delG突变的筛查试验的计算灵敏度和特异性分别为96.9%和97.4%，观察值分别为94%和97%。结论：我们的数据表明，GJB2突变是美国中西部中度至重度先天性遗传性耳聋的主要原因。GJB2基因突变的筛查对先天性耳聋患者具有较高的敏感性和特异性，仅筛查35delG基因突变，阳性结果应建立病因诊断并影响遗传咨询。
Context Mutations in the GJB2 gene are the most common known cause of inherited congenital severe-to-profound deafness, The carrier frequency of these mutations is not known.Objectives To determine the carrier rate of deafness-causing mutations in GJB2 in the midwestern United States and the prevalence of these mutations in persons with congenital sensorineural hearing loss ranging in severity from moderate to profound, and to derive revised data for counseling purposes.Design Laboratory analysis, performed in 1998, of samples from probands with hearing loss for mutations in GJB2 using an allele-specific polymerase chain reaction assay, single-strand conformation polymorphism analysis, and direct sequencing.Setting and Subjects Fifty-two subjects younger than 19 years sequentially referred to a midwestern tertiary referral center for hearing loss or cochlear implantation, with moderate-to-profound congenital hearing loss of unknown cause, parental nonconsanguinity, and nonsyndromic deafness with hearing loss limited to a single generation; 560 control neonates were screened for the 35delG mutation.Main Outcome Measure Prevalence of mutations in the GJB2 gene by congenital deafness status.Results Of 52 sequential probands referred for congenital sensorineural hearing loss, 22 (42%) were found to have GJB2 mutations. The 35delG mutation was identified in 29 of the 41 mutant alleles. Of probands' sibs, all homozygotes and compound heterozygotes had deafness. Fourteen of 560 controls were 35delG heterozygotes, for a carrier rate expressed as a mean (SE) of 2.5% (0.66%). The carrier rate for all recessive deafness-causing GJB2 mutations was determined to be 3.01% (probable range, 2.54%-3.56%). Calculated sensitivity and specificity for a screening test based on 35delG mutation alone were 96.9% and 97.4%, respectively, and observed values were 94% and 97%, respectively.Conclusions Our data suggest that mutations in GJB2 are the leading cause of moderate-to-profound congenital inherited deafness in the midwestern United States. Screening of the GJB2 mutation can be offered to individuals with congenital deafness with high sensitivity and specificity by screening only for the 35delG mutation,A positive finding should establish an etiologic diagnosis and affect genetic counseling.