Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Harvard Medical School Center for Hereditary Deafness, Boston, MA, USA.
Genet Med. 2019 Nov;21(11):2442-2452. doi: 10.1038/s41436-019-0535-9. Epub 2019 Jun 4.
Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.
The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed.
The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.
Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
GJB2 中的致病性变异是常染色体隐性遗传性感觉神经性听力损失的最常见原因。GJB2 中的 c.101T>C/p.Met34Thr 和 c.109G>A/p.Val37Ile 的分类存在争议。因此,需要专家共识来解释这两种变体。
ClinGen 听力损失专家小组收集了已发表的数据,并从参与的实验室和诊所共享了未发表的信息,这些信息与两种变体有关。还获得了功能、计算、等位基因和分离数据。进行了病例对照统计分析。
小组审查了综合信息,并利用专业的变异解释指南和专业判断对 p.Met34Thr 和 p.Val37Ile 变体进行了分类。我们发现,与人群对照相比,p.Met34Thr 和 p.Val37Ile 在听力损失患者中明显过表达。纯合子或复合杂合子 p.Met34Thr 或 p.Val37Ile 的个体通常表现为轻度至中度听力损失。其他几种类型的证据也支持这两种变体的致病性作用。
解决变异分类中的争议需要国际多机构专家小组的协调努力,以共享数据、标准化分类指南、审查证据并达成共识。我们得出结论,GJB2 中的 p.Met34Thr 和 p.Val37Ile 变体是常染色体隐性非综合征性听力损失的致病性变体,具有变异性表达和不完全外显率。