Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder.
Many hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood.



A total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype.



Well-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C > T (p.R425X) and one missense mutation c.4994 T > C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C > T (father and sister) and c.4994 T > C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region.



Two mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These findings not only extend the OTOF gene mutation spectrum for ANSD but also indicate that whole-exome sequencing is an effective approach to clarify the genetic characteristics in non-syndromic ANSD patients.
Department of Otolaryngology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
Fengzhu
F
Tang
CapitalBio Technology Co., Ltd., Building C, Block 88 Kechuang 6th Street, Yizhuang Biomedical Park, Beijing Economic- Technological Development Area, Beijing, 101111, China.
Dengke
D
Ma
CapitalBio Technology Co., Ltd., Building C, Block 88 Kechuang 6th Street, Yizhuang Biomedical Park, Beijing Economic- Technological Development Area, Beijing, 101111, China.
Yulan
Y
Wang
CapitalBio Technology Co., Ltd., Building C, Block 88 Kechuang 6th Street, Yizhuang Biomedical Park, Beijing Economic- Technological Development Area, Beijing, 101111, China.
Yuecai
Y
Qiu
Research Center of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
Fei
F
Liu
CapitalBio Technology Co., Ltd., Building C, Block 88 Kechuang 6th Street, Yizhuang Biomedical Park, Beijing Economic- Technological Development Area, Beijing, 101111, China.
Qingqing
Q
Wang
Department of Otolaryngology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
Qiutian
Q
Lu
Department of Otolaryngology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
Min
M
Shi
Department of Otolaryngology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
Liang
L
Xu
Department of Otolaryngology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
Min
M
Liu
Department of Otolaryngology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China. liangjpdoctor@163.com.
Jianping
0000-0002-2427-1820
J
Liang
D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics; D001309:Auditory Threshold; D002681:China; D018389:Codon, Nonsense; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D006313:Hearing Loss, Central / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
D018389:Codon, Nonsense; D008565:Membrane Proteins; C118457:OTOF protein, human; D004247:DNA
Auditory neuropathy spectrum disorder; Heterozygous mutations; OTOF gene; Whole-exome sequencing