TBC1D24 Mutation Causes Autosomal-Dominant Nonsyndromic Hearing Loss

• Published in: Human mutation Vol. 35; no. 7; pp. 819 - 823
• Main Authors: Azaiez, Hela, Booth, Kevin T., Bu, Fengxiao, Huygen, Patrick, Shibata, Seiji B., Shearer, A. Eliot, Kolbe, Diana, Meyer, Nicole, Black-Ziegelbein, E. Ann, Smith, Richard J.H.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-07-2014; Hindawi Limited
• Subjects: Amino Acid Sequence; autosomal dominant; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Deafness - genetics; DNA Mutational Analysis; Exome; Female; Gene Expression; Genes, Dominant; Genetic disorders; hearing impairment; Hearing loss; Hearing protection; High-Throughput Nucleotide Sequencing; Humans; Male; Molecular Sequence Data; Mutation; nonsyndromic; OtoSCOPE; Pedigree; pleiotropy; Sequence Alignment; TBC1D24; OtoSCOPE; nonsyndromic; TBC1D24; hearing impairment; hearing loss; autosomal dominant; pleiotropy
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22557

ABSTRACT
Hereditary hearing loss is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal‐dominant nonsyndromic hearing loss (NSHL), we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole‐exome sequencing to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase‐activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL, syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS syndrome), and a wide range of epileptic disorders.
After excluding mutations in all genes implicated in non‐syndromic hearing loss, we completed segregation mapping and whole exome sequencing on 7 and 3 persons, respectively. WES data were hard filtered to identify 46 variants shared by the 3 affecteds, only one of which mapped to a segregating genomic interval. The Ser178Leu variant in TBC1D24 is highly conserved across species. The transcribed gene is expressed in inner and outer hair cells in the P2 mouse cochlea (green; actin, red; DAPI, blue).