Open AccessNovel loss-of-function mutations in COCH cause autosomal recessive nonsyndromic hearing loss
Author(s) -
Kevin T. Booth,
Amama Ghaffar,
Maryam Rashid,
Luke T Hovey,
Mureed Hussain,
Kathy Frees,
Erika M Renkes,
Carla Nishimura,
Mohsin Shahzad,
Richard J.H. Smith,
Zubair M. Ahmed,
Héla Azaiez,
Saima Riazuddin
Publication year - 2020
Publication title -
human genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.351
H-Index - 137
eISSN - 1432-1203
pISSN - 0340-6717
DOI - 10.1007/s00439-020-02197-5
Subject(s) - minigene , biology , genetics , hearing loss , exon skipping , exon , missense mutation , rna splicing , nonsense mutation , loss function , nonsense , gene , haploinsufficiency , exome sequencing , sensorineural hearing loss , alternative splicing , mutation , rna , phenotype , medicine , audiology
COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing, and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense, and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used minigene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.