Cryns K, Orzan E, Murgia A, Huygen P L M, Moreno F, del Castillo I, Chamberlin G Parker, Azaiez H, Prasad S, Cucci R A, Leonardi E, Snoeckx R L, Govaerts P J, Van de Heyning P H, Van de Heyning C M, Smith R J H, Van Camp G
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
J Med Genet. 2004 Mar;41(3):147-54. doi: 10.1136/jmg.2003.013896.
Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test.
To assess a possible genotype-phenotype correlation for GJB2.
Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations.
Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations.
We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes.
This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.
GJB2基因的突变是导致非综合征性常染色体隐性听力障碍的最常见原因，听力障碍程度从轻度到重度不等。该基因的突变分析作为一种基因诊断测试广泛可用。
评估GJB2基因可能存在的基因型与表型的相关性。
对听力障碍患者的听力测定数据进行回顾性分析，这些患者存在两种GJB2基因突变。
277名无亲缘关系的听力障碍患者，他们来自意大利、比利时、西班牙和美国的地方及大学医院的耳鼻喉科，且携带双等位基因GJB2突变。
我们发现，与35delG/非35delG复合杂合子相比，35delG纯合子的听力障碍明显更严重。具有两个非35delG突变的患者听力障碍甚至更轻。当我们将突变分类为失活突变（即终止突变或移码突变）或非失活突变（即错义突变）时，我们观察到了类似的听力障碍梯度。我们证明，与35delG纯合基因型相比，某些突变组合（包括35delG与错义突变L90P、V37I或剪接位点突变IVS1+1G>A的组合，以及V37I/V37I基因型）与明显较轻的听力障碍相关。
本研究是首次大规模系统分析，表明GJB2基因型对听力障碍程度有重大影响，并确定了轻度基因型。此外，本研究表明有可能进一步完善这种相关性并将其扩展到其他基因型。这些数据将有助于评估GJB2相关耳聋患者的康复选择。
