The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study

被引：12

作者：

Thorpe, Ryan K. ^{[1
]}

Azaiez, Hela ^{[1
]}

Wu, Peina ^{[2
]}

Wang, Qiuju ^{[3
]}

Xu, Lei ^{[4
]}

Dai, Pu ^{[5
]}

Yang, Tao ^{[6
]}

Schaefer, G. Bradley ^{[7
]}

Peters, B. Robert ^{[8
]}

Chan, Kenny H. ^{[9
]}

Schatz, Krista S. ^{[10
]}

Bodurtha, Joann ^{[10
]}

Robin, Nathaniel H. ^{[11
]}

Hirsch, Yoel ^{[12
]}

Rahbeeni, Zuhair Abdalla ^{[13
]}

Yuan, Huijun ^{[14
]}

Smith, Richard J. H. ^{[1
,15
]}

机构：

[1] Univ Iowa, Mol Otolaryngol & Renal Res Labs, Dept Otolaryngol Head & Neck Surg, Carver Coll Med, Iowa City, IA 52242 USA

[2] Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Dept Otolaryngol, Guangzhou, Peoples R China

[3] Natl Clin Res Ctr Otolaryngol Dis, Chinese PLA Gen Hosp, Chinese PLA Med Sch,Chinese PLA Inst Otolaryngol, Coll Otolaryngol Head & Neck Surg, Beijing 100853, Peoples R China

[4] Shandong Univ, Shandong Prov ENT Hosp, Cheeloo Coll Med, Jinan, Peoples R China

[5] Chinese PLA Med Sch, Coll Otolaryngol Head & Neck Surg, Chinese PLA Gen Hosp, Beijing, Peoples R China

[6] Shanghai Jiao Tong Univ, Peoples Hosp 9, Sch Med, Shanghai, Peoples R China

[7] Univ Arkansas Med Sci, Little Rock, AR 72205 USA

[8] Dallas Hearing Fdn, Dallas Ear Inst, Dallas, TX USA

[9] Childrens Hosp Colorado, Dept Pediat Otolaryngol, Aurora, CO USA

[10] Johns Hopkins Med Inst, McKusick Nathans Dept Genet Med, Baltimore, MD USA

[11] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA

[12] Dor Yeshorim, Comm Preventing Jewish Genet Dis, Brooklyn, NY USA

[13] King Faisal Specialist Hosp & Res Ctr, Med Genet Dept, Riyadh, Saudi Arabia

[14] Army Med Univ, Southwest Hosp, Med Genet Ctr, Chongqing, Peoples R China

[15] Univ Iowa, Interdisciplinary Grad Program Genet, Iowa City, IA 52242 USA

来源：

HUMAN GENETICS | 2022年 / 141卷 / 3-4期

关键词：

NONSYNDROMIC HEARING-LOSS; OTOFERLIN GENE OTOF; COCHLEAR IMPLANTATION; ENCODING OTOFERLIN; LOW-PREVALENCE; MUTATIONS; DEAFNESS; GJB2; IDENTIFICATION; CHILDREN;

D O I：

10.1007/s00439-021-02340-w

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Pathogenic variations in the OTOF gene are a common cause of hearing loss. To refine the natural history and genotype-phenotype correlations of OTOF-related auditory neuropathy spectrum disorders (ANSD), audiograms and distortion product otoacoustic emissions (DPOAEs) were collected from a diverse cohort of individuals diagnosed with OTOF-related ANSD by comprehensive genetic testing and also reported in the literature. Comparative analysis was undertaken to define genotype-phenotype relationships using a Monte Carlo algorithm. 67 audiograms and 25 DPOAEs from 49 unique individuals positive for OTOF-related ANSD were collected. 51 unique OTOF pathogenic variants were identified of which 21 were missense and 30 were loss of function (LoF; nonsense, splice-site, copy number variants, and indels). There was a statistically significant difference in low, middle, and high frequency hearing thresholds between missense/missense and LoF/missense genotypes as compared to LoF/LoF genotypes (average hearing threshold for low, middle and high frequencies 70.9, 76.0, and 73.4 dB vs 88.5, 95.6, and 94.7 dB) via Tukey's test with age as a co-variate (P = 0.0180, 0.0327, and 0.0347, respectively). Hearing declined during adolescence with missense/missense and LoF/missense genotypes, with an annual mid-frequency threshold deterioration of 0.87 dB/year and 1.87 dB/year, respectively. 8.5% of frequencies measured via DPOAE were lost per year in individuals with serial tests. Audioprofiling of OTOF-related ANSD suggests significantly worse hearing with LoF/LoF genotypes. The unique pattern of variably progressive OTOF-related autosomal recessive ANSD may be amenable to gene therapy in selected clinical scenarios.

引用

页码：853 / 863

页数：11

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