Abstract
SummaryBackgroundNon-syndromic autosomal dominant hearing impairment is characteristically postlingual in onset. Genetic diagnostics are essential for genetic counselling, disease prognosis and understanding of the molecular mechanisms of disease. To date, 36 causative genes have been identified, many in only individual families. Gene selection for genetic screening by traditional methods and genetic diagnosis in autosomal dominant patients has therefore been fraught with difficulty. Whole-exome sequencing provides a powerful tool to analyze all protein-coding genomic regions in parallel, thus allowing the comprehensive screening of all known genes and associated alterations.MethodsIn this study, a previously undiagnosed late-onset progressive autosomal dominant hearing loss in an Austrian family was investigated by means of whole-exome sequencing. Results were confirmed by Sanger sequencing.ResultsA previously described c.151C>T missense (p.Pro51Ser) mutation in the LCCL (limulus factor C, cochlin, late gestation lung protein Lgl1) domain of the cochlin gene (COCH) was identified as causative and segregated with disease in five members of the family. Molecular diagnostics led to the decision to perform cochlear implantation in an index patient who subsequently showed excellent postoperative auditory performance. The c.151C>T mutation was not found in 18 screened Austrian families with autosomal dominant hearing loss but was represented alongside other known pathogenic mutant COCH alleles in the Genome Aggregation Database (gnomAD) in European populations. A combined allele frequency of 0.000128 implies an orphan disease frequency for COCH-induced hearing loss of 1:3900 in Europe.ConclusionsExome sequencing successfully resolved the genetic diagnosis in a family suffering from autosomal dominant hearing impairment and allowed prediction of purported auditory outcome after cochlear implantation in an index patient. Personalized treatment approaches based on the molecular mechanisms of disease may become increasingly important in the future.
Highlights
Hereditary hearing impairment (HI) is a heterogenous disease that can vary in degree of disability, time of onset, accompanying symptoms, mode of inheritance and underlying molecular pathomechanism
We demonstrate by a case report of one of the family members how the molecular diagnostics helped to predict cochlear implant performance and aided in the clinical decision to perform bilateral Electroacoustic stimulation (EAS) cochlear implant surgery in the patient
Variant analysis in the index patient (III/7) revealed a heterozygous missense c.151C>T mutation in the cochlin gene (COCH) that has been previously reported to cause progressive late-onset HI in Dutch, Belgian and US families ([17,18,19,20,21]; Fig. 1). This single nucleotide alteration leads to an amino acid exchange from proline to serine at position 51 of the mature cochlin peptide (p.Pro51Ser)
Summary
Hereditary hearing impairment (HI) is a heterogenous disease that can vary in degree of disability, time of onset, accompanying symptoms, mode of inheritance and underlying molecular pathomechanism. Dominant forms of genetic HI amount to almost 20% of cases In the latter group, HI usually develops at different stages of life and gradually progresses over time. Unlike congenital recessive forms, no common causative genes have been identified for dominant late-onset progressive HI, making gene selection for genetic screening of dominant cases challenging. To reduce the costs of analysis and sequencing data loads, targeted capture of known HI genes and whole-exome sequencing (WES) have been successfully applied to identify causative genes and alterations in HI cohorts from numerous populations [3,4,5]
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