Cesca Federica, Bettella Elisa, Polli Roberta, Cama Elona, Scimemi Pietro, Santarelli Rosamaria, Murgia Alessandra
Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padova, Italy.
Audiology and Phoniatrics Service, Treviso Regional Hospital, Italy; Neuroscience Department, University of Padova, Italy.
Int J Pediatr Otorhinolaryngol. 2018 Jan;104:88-93. doi: 10.1016/j.ijporl.2017.10.042. Epub 2017 Oct 31.
This work was aimed at establishing the molecular etiology of hearing loss in a 9-year old girl with post-lingual non-syndromic mild sensorineural hearing loss with a complex family history of clinically heterogeneous deafness.
The proband's DNA was subjected to NGS analysis of a 59-targeted gene panel, with the use of the Ion Torrent PGM platform. Conventional Sanger sequencing was used for segregation analysis in all the affected relatives. The proband and all the other hearing impaired members of the family underwent a thorough clinical and audiological evaluation.
A new likely pathogenic mutation in the EYA4 gene (c.1154C > T; p.Ser385Leu) was identified in the proband and in her 42-year-old father with post-lingual non-syndromic profound sensorineural hearing loss. The EYA4 mutation was also found in the proband's grandfather and uncle, both showing clinical features of Waardenburg syndrome type 1. A novel pathogenic splice-site mutation (c.321+1G > A) of the PAX3 gene was found to co-segregate with the EYA4 mutation in these two subjects.
The identified novel EYA4 mutation can be considered responsible of the hearing loss observed in the proband and her father, while a dual molecular diagnosis was reached in the relatives co-segregating the EYA4 and the PAX3 mutations. In these two subjects the DFNA10 phenotype was masked by Waardenburg syndrome. The use of NGS targeted gene-panel, in combination with an extensive clinical and audiological examination led us to identify the genetic cause of the hearing loss in members of a family in which different forms of autosomal dominant deafness segregate. These results provide precise and especially important prognostic and follow-up information for the future audiologic management in the youngest affected member.
本研究旨在确定一名9岁女童听力损失的分子病因，该女童患有语后非综合征性轻度感音神经性听力损失，且有临床异质性耳聋的复杂家族病史。
利用Ion Torrent PGM平台，对先证者的DNA进行59个靶向基因 panel的NGS分析。采用传统的桑格测序法对所有受影响亲属进行分离分析。先证者和家族中所有其他听力受损成员均接受了全面的临床和听力学评估。
在先证者及其42岁患有语后非综合征性重度感音神经性听力损失的父亲中，发现了EYA4基因的一个新的可能致病突变（c.1154C>T；p.Ser385Leu）。在先证者的祖父和叔叔中也发现了EYA4突变，他们均表现出1型瓦登伯革综合征的临床特征。在这两名受试者中，发现PAX3基因的一个新的致病剪接位点突变（c.321+1G>A）与EYA4突变共分离。
所鉴定的新型EYA4突变可被认为是先证者及其父亲听力损失的原因，而在共分离EYA4和PAX3突变的亲属中达成了双重分子诊断。在这两名受试者中，DFNA10表型被瓦登伯革综合征所掩盖。使用NGS靶向基因panel，结合广泛的临床和听力学检查，使我们能够确定一个家族中不同形式的常染色体显性耳聋分离的成员听力损失的遗传原因。这些结果为最年轻的受影响成员未来的听力学管理提供了精确且特别重要的预后和随访信息。
