关键词： ARNSHL, autosomal recessive non-syndromic hearing loss Actb, Actin beta BAM, Binary Alignment Map BWA, Burrows-Wheeler Aligner C1QTNF9, C1q and TNF related 9 Cx26, Connexin 26 ESRRAP2, Estrogen-Related Receptor Alpha Pseudogene 2 GJB2 gene GJB2, Gap Junction Protein Beta 2 HHLA1, HERV-H LTR-Associating 1 HL, Hearing loss KCNQ3, Potassium Voltage-Gated Channel Subfamily Q Member 3 Missense mutation NGS, next generation sequencing NSHL, Non-syndromic hearing loss Non-syndromic hearing loss PROVEAN, Protein Variation Effect Analyzer PolyPhen-2, Polymorphism Phenotyping v2 RFLP, restriction fragment length polymorphism ROH, runs of homozygosity RT-PCR, reverse transcription PCR RT-qPCR, quantitative reverse transcription PCR SAM, Sequence Alignment/Map SIFT, Sorting Intolerant From Tolerant SJL, Swiss Jim Lambert SPATA13, Spermatogenesis Associated 13 ST3GAL1, ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 1 TMEM59, Transmembrane Protein 59 UAE, United Arab Emirates VariMAT, Variation and Mutation Annotation Toolkit WES, Whole exome sequencing Whole exome sequencing dpSNP, Single Nucleotide Polymorphism Database gEAR, gene Expression Analysis Resource gnomAD, genome aggregation database qPCR, quantitative PCR

来  源：   DOI：10.1016/j.sjbs.2021.04.036   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
The development of next generation sequencing techniques has facilitated the detection of mutations at an unprecedented rate. These efficient tools have been particularly beneficial for extremely heterogeneous disorders such as autosomal recessive non-syndromic hearing loss, the most common form of genetic deafness. GJB2 mutations are the most common cause of hereditary hearing loss. Amongst them the NM_004004.5: c.506G > A (p.Cys169Tyr) mutation has been associated with varying severity of hearing loss with unclear segregation patterns. In this study, we report a large consanguineous Emirati family with severe to profound hearing loss fully segregating the GJB2 missense mutation p.Cys169Tyr. Whole exome sequencing (WES), in silico, splicing and expression analyses ruled out the implication of any other variants and confirmed the implication of the p.Cys169Tyr mutation in this deafness family. We also show preliminary murine expression analysis that suggests a link between the TMEM59 gene and the hearing process. The present study improves our understanding of the molecular pathogenesis of hearing loss. It also emphasizes the significance of combining next generation sequencing approaches and segregation analyses especially in the diagnosis of disorders characterized by complex genetic heterogeneity.
摘要：
下一代测序技术的发展促进了以前所未有的速度检测突变。这些有效的工具对极端异质性的疾病特别有益，例如常染色体隐性遗传的非综合征性听力损失，最常见的遗传性耳聋.GJB2突变是遗传性听力损失的最常见原因。其中NM_004004.5：c.506G>A（p。Cys169Tyr）突变与不同严重程度的听力损失相关，分离模式不清楚。在这项研究中,我们报告了一个大型近亲阿联酋家族，患有严重至严重的听力损失，完全隔离了GJB2错义突变p.Cys169Tyr。全外显子组测序(WES),在硅，剪接和表达分析排除了任何其他变体的含义，并证实了该耳聋家族中p.Cys169Tyr突变的含义。我们还显示了初步的鼠表达分析，表明TMEM59基因与听力过程之间存在联系。本研究提高了我们对听力损失分子发病机制的认识。它还强调了结合下一代测序方法和分离分析的重要性，特别是在诊断以复杂遗传异质性为特征的疾病中。
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