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Original Investigation |

Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss

Christina L. Runge, PhD1; Amit Indap, PhD2; Yifan Zhou, PhD3; Jack W. Kent Jr, PhD4; Ericka King, MD1; Christy B. Erbe, BS1; Regina Cole, BS5; Jack Littrell, MS5; Kate Merath, PhD5; Roland James, MS5; Franz Rüschendorf, PhD6; Joseph E. Kerschner, MD1; Gabor Marth, PhD7; Norbert Hübner, PhD6; Harald H. H. Göring, PhD4; David R. Friedland, MD, PhD1; Wai-Meng Kwok, PhD3,8; Michael Olivier, PhD4,5
[+] Author Affiliations
1Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee
2Department of Biology, Boston College, Chestnut Hill, Massachusetts
3Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee
4Department of Genetics, Texas Biomedical Research Institute, San Antonio
5Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee
6Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany
7Department of Human Genetics, University of Utah School of Medicine, Salt Lake City
8Department of Anesthesiology, Medical College of Wisconsin, Milwaukee
JAMA Otolaryngol Head Neck Surg. 2016;142(9):866-872. doi:10.1001/jamaoto.2016.1444.
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Importance  Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL.

Objective  To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent.

Design, Setting, and Participants  In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined.

Main Outcomes and Measures  Sensorineural hearing loss.

Results  Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 × 10−4).

Conclusions and Relevance  A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.

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Figure 1.
Pedigree of a Family With Sensorineural Hearing Loss

Hearing loss status was self-reported, reported by family members (for deceased and very young individuals), or based on records of audiometric tests. Individuals who provided audiometric records were III:7, IV:5, IV:6, IV:7, IV:9, IV:10, IV:13, V:7, and V:11. Hearing loss was self-reported for III:5, IV:3, IV:8 (before death), V:3, and V:5. Family members reported hearing loss for II:2, II:3, III:2, III:3, and VI:1. Deceased individuals with unknown hearing loss cause are indicated by gray symbols; all affected individuals are represented by filled symbols.

aIndividuals included in the initial linkage analysis.

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Figure 2.
Hearing Loss Phenotype

A and B, Serial audiograms showing progressive hearing loss from the right ear of 2 family members representing different generations. C, Audiograms from 3 unrelated individuals with sensorineural hearing loss (SNHL) who harbor the same mutation found in the Wisconsin family. D, Age-related typical audiograms calculated from right-ear audiograms of affected family members. db HL indicates decibels Hearing Level.

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Figure 3.
Genome-Wide Linkage Plot

The logarithm of odds (LOD) score from a 2-point linkage analysis of all 631 644 single-nucleotide polymorphisms in 20 individuals of the sensorineural hearing loss family are shown relative to the chromosomal location of each variant.

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Figure 4.
Reverse Transcription–Polymerase Chain Reaction Gene Expression Analysis From Human Inner Ear Tissue

Cycle threshold (Ct) values for TMTC2 are shown in dark blue, and Ct values for a reference gene, HPRT, are shown in light blue. Higher Ct values indicate lower gene expression levels. No target and no reverse transcription controls had no signal after 50 cycles. Error bars indicate SE.

Graphic Jump Location

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