A novel mutation of the EYA4 gene associated with post-lingual hearing loss in a proband is co-segregating with a novel PAX3 mutation in two congenitally deaf family members.
OBJECTIVES
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.


METHODS
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.


RESULTS
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.


CONCLUSION
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.
['Cesca|Federica|F|', 'Bettella|Elisa|E|', 'Polli|Roberta|R|', 'Cama|Elona|E|', 'Scimemi|Pietro|P|', 'Santarelli|Rosamaria|R|', 'Murgia|Alessandra|A|']
D000328:Adult D001299:Audiometry D002648:Child D003638:Deafness D005190:Family D005260:Female D006319:Hearing Loss, Sensorineural D059014:High-Throughput Nucleotide Sequencing D006801:Humans D008297:Male D009154:Mutation D000072041:PAX3 Transcription Factor D010375:Pedigree D010641:Phenotype D015534:Trans-Activators D014849:Waardenburg Syndrome
EYA4 PAX3 Waardenburg syndrome type 1 Next Generation Sequencing Non-syndromic hearing loss