Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss.
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.



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



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.



Sensorineural hearing loss.



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).



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.
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee.
Christina L
CL
Runge
Department of Biology, Boston College, Chestnut Hill, Massachusetts.
Amit
A
Indap
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.
Yifan
Y
Zhou
Department of Genetics, Texas Biomedical Research Institute, San Antonio.
Jack W
JW
Kent
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee.
Ericka
E
King
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee.
Christy B
CB
Erbe
Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee.
Regina
R
Cole
Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee.
Jack
J
Littrell
Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee.
Kate
K
Merath
Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee.
Roland
R
James
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
Franz
F
Rüschendorf
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee.
Joseph E
JE
Kerschner
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City.
Gabor
G
Marth
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
Norbert
N
Hübner
Department of Genetics, Texas Biomedical Research Institute, San Antonio.
Harald H H
HH
Göring
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee.
David R
DR
Friedland
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee8Department of Anesthesiology, Medical College of Wisconsin, Milwaukee.
Wai-Meng
WM
Kwok
Department of Genetics, Texas Biomedical Research Institute, San Antonio5Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee.
Michael
M
Olivier
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12; D018450:Disease Progression; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006312:Hearing Loss, Bilateral / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011446:Prospective Studies; D044465:White People / Q000235:genetics; D055815:Young Adult
D002352:Carrier Proteins; D008565:Membrane Proteins; C000592187:TMTC2 protein, human