Usher综合征包括一组具有听力缺陷和色素性视网膜炎的遗传和临床异质性常染色体隐性遗传疾病。Usher综合征的潜在机制是高度可变的。在本研究中,招募了一个患有Usher综合征的中国家庭。全外显子组测序(WES),桑格测序,纯合性映射,进行了短串联重复(STR)分析和偏析分析。分析了USH2A的致病变体的功能域。我们确定了纯合移码变体c.99_100insT(p。先证者中的USH2A基因中的Arg34Serfs*41)在父亲中显示不一致的隔离。进一步的纯合性作图和STR分析鉴定了起源于母体单亲二体(UPD)的先证者的不寻常纯合变体。p.Arg34Serfs*41变体产生预测的截短蛋白,其去除USH2A的所有功能结构域。该变体未包含在1000人类基因组计划数据库中,ExAC数据库,HGMD或gnomAD数据库,但作为致病性被纳入ClinVar数据库。尽管USH2A是一种常染色体隐性疾病,UPD的影响应在遗传咨询中告知,因为当疾病是由UPD机制引起时,受影响儿童的复发风险大大降低.为了测试潜在的病人,WES,结合STR分析和纯合性映射,为基因诊断提供了一种准确有用的战略。总之,我们的发现有助于进一步了解Usher综合征IIA的分子发病机制,这种疾病的诊断和治疗。
Usher syndrome encompasses a group of genetically and clinically heterogeneous autosomal recessive disorders with hearing deficiencies and retinitis pigmentosa. The mechanisms underlying the Usher syndrome are highly variable. In the present study, a Chinese family with Usher syndrome was recruited. Whole exome sequencing (WES), Sanger sequencing, homozygosity mapping, short tandem repeat (STR) analysis and segregation analysis were performed. Functional domains of the pathogenic variant for USH2A were analysed. We identified a homozygous frameshift variant c.99_100insT (p.Arg34Serfs*41) in the USH2A gene in the proband that showed discordant segregation in the father. Further homozygosity mapping and STR analysis identified an unusual homozygous variant of proband that originated from maternal uniparental disomy (UPD). The p.Arg34Serfs*41 variant produced a predicted truncated protein that removes all functional domains of USH2A. The variant was not included in the 1000 Human Genomes Project database, ExAC database, HGMD or gnomAD database, but was included in the ClinVar databases as pathogenic. Although USH2A is an autosomal recessive disease, the effects of UPD should be informed in genetic counselling since the recurrence risk of an affected child is greatly reduced when the disease is due to the UPD mechanism. To test potential patients, WES, combined with STR analysis and homozygosity mapping, provides an accurate and useful strategy for genetic diagnosis. In summary, our discoveries can help further the understanding of the molecular pathogenesis of Usher syndrome type IIA to advance the prevention, diagnosis and therapy for this disorder.