Dataset Information

Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss.

ABSTRACT: 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.

SUBMITTER: Runge CL

PROVIDER: S-EPMC5025373 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss.

Runge Christina L CL Indap Amit A Zhou Yifan Y Kent Jack W JW King Ericka E Erbe Christy B CB Cole Regina R Littrell Jack J Merath Kate K James Roland R Rüschendorf Franz F Kerschner Joseph E JE Marth Gabor G Hübner Norbert N Göring Harald H H HH Friedland David R DR Kwok Wai-Meng WM Olivier Michael M

JAMA otolaryngology-- head & neck surgery 20160901 9

<h4>Importance</h4>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.<h4>Objective</h4>To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent.<h4>D ...[more]

PMID: 27311106

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Project description:BackgroundHereditary hearing loss (HL) is heterogeneous in terms of their phenotypic features, modes of inheritance, and causative gene mutations. The contribution of genetic variants to sporadic HL remains largely expanding. Either recessive or de novo dominant variants could result in an apparently sporadic occurrence of HL. In an attempt to find such variants we recruited 128 Chinese patients with sporadic nonsyndromic sensorineural HL (NSHL) and performed targeted deafness multigene sequencing in these unrelated trios-families to elucidate the molecular basis.MethodsWe analyzed a total of 384 available members (probands and their two parents) from 128 unrelated Chinese families presenting with bilateral sensorineural HL, in which previous screening had found no mutations with the GJB2, SLC26A4, and MT-RNR1 genes. We used a targeted genomic enrichment platform to simultaneously capture exons, splicing sites, and immediate flanking intron sequences of 127 known deafness genes. Sanger sequencing was used to identify probands and their two parents segregating causative variants in the candidate gene.ResultsWe observed that two heterozygous de novo WFS1 mutations in exon 8: c.2051C>T (p.A684V) and c.2590G>A (p.E864K) in five families. The two de novo WFS1 mutations were found in 3.9% (5/128) of sporadic HL patients. We found that four of the five patients had the same de novo p.A684V mutation, and their audiograms showed symmetrical bilateral and profound sensorineural hearing impairments at all frequencies, but only the proband with de novo p.E864K mutation demonstrated significantly bilateral moderate low-mid frequency sensorineural HL. Our data suggest that this WFS1 p.A684V is likely to be a de novo mutational hot spot.ConclusionsWe found 3.9% (5/128) of sporadic NSHL is caused by de novo WFS1 mutations. Our data provide that the de novo p.E864K mutation is first identified and de novo p.A684V mutation is likely to be a mutational hot spot in WFS1. It is the first study to highlight that WFS1 gene with the two de novo mutations has been indicated to classify the distinct hearing impairment phenotypes. Furthermore, de novo p.A684V serves as a WFS1 mutational hot spot that was found in the Chinese population with sporadic childhood NSHL, and our study also provides pointers toward the necessity for sequencing of asymptomatic parents of a sporadic case with an apparent dominant pathogenic variant.

Project description:ImportancePatients with idiopathic sudden sensorineural hearing loss (ISSNHL) often experience permanent hearing impairment, which could result in psychological perturbations. However, the relationship between ISSNHL and affective disorders, including depression, anxiety, and bipolar disorder, has not been fully evaluated.ObjectiveTo investigate the potential relationship between ISSNHL and affective disorders using nationwide representative cohort sample data.Design, setting, and participantsThis study used a nationwide propensity score-matched cohort sample from the Korean National Health Insurance Service database from 2002 through 2013, which comprises data from approximately 1 million patients. The study included 1425 patients with ISSNHL and 7125 individuals without ISSNHL who were matched using propensity score matching, according to sociodemographic factors and enrollment year.Main outcomes and measuresSurvival analysis, the log-rank test, and Cox proportional hazards regression models were used to calculate the incidence, survival rate, and hazard ratio (HR) of developing affective disorders (anxiety, depression, and bipolar disorder) for each group.ResultsOf the total study population of 8550 (51.5% female), 961 developed affective disorders during the 11-year follow-up: 225 in the ISSNHL group (15.8%) and 736 in the comparison group (10.3%). We examined a total of 96 885.5 person-years (81 177.4 person-years in the comparison group and 15 708.1 person-years in the ISSNHL group). The incidence of affective disorders was 14.3 per 1000 person-years in the ISSNHL group and 9.1 per 1000 person-years in the comparison group. After adjustment for other factors, individuals with ISSNHL developed affective disorders more frequently than those in the comparison group (HR, 1.50; 95% CI, 1.30-1.75). Among the affective disorders, the HR of developing depression (HR, 1.66; 95% CI, 1.44-1.91) and anxiety disorder (HR, 1.79; 95% CI, 1.56-2.05) but not bipolar disorder (HR, 0.95; 95% CI, 0.54-1.70), was significantly greater in patients with ISSNHL.Conclusions and relevanceThis cohort study suggests that ISSNHL is associated with an increased incidence of affective disorders, specifically depression and anxiety. Therefore, these findings suggest that clinicians should monitor patients with ISSNHL carefully, and take specific precautions to reduce their risk of depression and anxiety disorder.

Dataset Information

Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss.

Publications

Association of TMTC2 With Human Nonsyndromic Sensorineural Hearing Loss.

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