Hearing Levels in the Patient Groups with the Homozygous and Compound p.V37I Variant.

<p>The Friedman rank-sum test (M-test) was used to identify significant differences in hearing level among the groups, and H = 0.4375, P>0.25.</p><p>Hearing Levels in the Patient Groups with the Homozygous and Compound p.V37I Variant.</p

Distribution of the p.V37I Variation in the Patient and Control Groups.

<p>Distribution of the p.V37I Variation in the Patient and Control Groups.</p

The Relationship between the p.V37I Mutation in <i>GJB2</i> and Hearing Phenotypes in Chinese Individuals

<div><p>The most common cause of nonsyndromic autosomal recessive hearing loss is mutations in <i>GJB2</i>. The mutation spectrum and prevalence of mutations vary significantly among ethnic groups, and the relationship between p.V37I mutation in <i>GJB2</i> and the hearing phenotype is controversial. Among the 3,864 patients in this study, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other <i>GJB2</i> pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). The hearing loss phenotype ranged from mild to profound in all patients with the homozygous p.V37I variation or compound p.V37I plus other <i>GJB2</i> pathogenic mutation. There was no difference in the distribution of the hearing level in the group with the homozygous p.V37I variation and the group with the compound p.V37I variation plus pathogenic mutation. Most patients (66.04%) with the V37I-homozygous variation or p.V37I plus other pathogenic mutation had a mild or moderate hearing level. This study found a definite relationship between p.V37I and deafness, and most patients who carried the pathogenic combination with p.V37I mutation had mild or moderate hearing loss. Therefore, otolaryngologists should consider that the milder phenotype might be caused by the <i>GJB2</i> p.V37I mutation.</p></div

Hearing levels of patients with the p.V37I/c.235delC compound heterozygous variation.

<p>Hearing levels of patients with the p.V37I/c.235delC compound heterozygous variation.</p

Distribution of Compound p.V37I Plus other GJB2 Pathogenic Mutation in the Patient Group.

<p>Distribution of Compound p.V37I Plus other GJB2 Pathogenic Mutation in the Patient Group.</p

Additional file 1: of Phenotypic Heterogeneity in a DFNA20/26 family segregating a novel ACTG1 mutation

Questionnaire for deafness. (DOCX 14 kb

<i>KCNJ10</i> May Not Be a Contributor to Nonsyndromic Enlargement of Vestibular Aqueduct (NSEVA) in Chinese Subjects

<div><p>Background</p><p>Nonsyndromic enlargement of vestibular aqueduct (NSEVA) is an autosomal recessive hearing loss disorder that is associated with mutations in <i>SLC26A4</i>. However, not all patients with NSEVA carry biallelic mutations in <i>SLC26A4</i>. A recent study proposed that single mutations in both <i>SLC26A4</i> and <i>KCNJ10</i> lead to digenic NSEVA. We examined whether <i>KCNJ10</i> excert a role in the pathogenesis of NSEVA in Chinese patients.</p><p>Methods</p><p><i>SLC26A4</i> was sequenced in 1056 Chinese patients with NSEVA. <i>KCNJ10</i> was screened in 131 patients who lacked mutations in either one or both alleles of <i>SLC26A4.</i> Additionally, <i>KCNJ10</i> was screened in 840 controls, including 563 patients diagnosed with NSEVA who carried biallelic <i>SLC26A4</i> mutations, 48 patients with nonsyndromic hearing loss due to inner ear malformations that did not involve enlargement of the vestibular aqueduct (EVA), 96 patients with conductive hearing loss due to various causes, and 133 normal-hearing individuals with no family history of hereditary hearing loss.</p><p>Results</p><p>925 NSEVA patients were found carrying two-allele pathogenic <i>SLC26A4</i> mutations. The most frequently detected <i>KCNJ10</i> mutation was c.812G>A (p.R271H). Compared with the normal-hearing control subjects, the occurrence rate of c.812G>A in NSEVA patients with lacking mutations in one or both alleles of <i>SLC26A4</i> had no significant difference(1.53% vs. 5.30%, χ² = 2.798, p = 0.172), which suggested that it is probably a nonpathogenic benign variant. <i>KCNJ10</i> c.1042C>T (p.R348C), the reported EVA-related mutation, was not found in patients with NSEVA who lacked mutations in either one or both alleles of <i>SLC26A4.</i> Furthermore, the normal-hearing parents of patients with NSEVA having two <i>SLC26A4</i> mutations carried the <i>KCNJ10</i> c.1042C>T or c.812G>A mutation and a <i>SLC26A4</i> pathogenic mutation.</p><p>Conclusion</p><p><i>SLC26A4</i> is the major genetic cause in Chinese NSEVA patients, accounting for 87.59%. <i>KCNJ10</i> may not be a contributor to NSEVA in Chinese population. Other genetic or environmental factors are possibly play a role in the etiology of Chinese EVA patients with zero or monoallelic <i>SLC26A4</i> mutation.</p></div

Pedigrees of the Chinese WS2 families WS01, WS02, and WS03, and audiograms of some affected male and female subjects.

<p>High clinical variability was observed even within the same family. Not all affected persons manifested all clinical features. Circle, female; square, male; filled quadrants indicate phenotype associated with WS, upper left, premature graying hair; lower left, freckles on the skin; upper right, hearing loss; lower right, heterochromia iridis; arrow, the proband; *, DNA samples available.</p

Genetic and Phenotypic Heterogeneity in Chinese Patients with Waardenburg Syndrome Type II

<div><p>Waardenburg Syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (<i>MITF</i>) gene mutations account for about 15% of WS type II (WS2) cases. To date, fewer than 40 different <i>MITF</i> gene mutations have been identified in human WS2 patients, and few of these were of Chinese descent. In this study, we report clinical findings and mutation identification in the <i>MITF</i> gene of 20 Chinese WS2 patients from 14 families. A high level of clinical variability was identified. Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. Five affected individuals (5/20, 25.0%) had numerous brown freckles on the face, trunk, and limb extremities. Mutation screening of the <i>MITF</i> gene identified five mutations: c.20A>G, c.332C>T, c.647_649delGAA, c.649A>G, and c.763C>T. The total mutational frequency of the <i>MITF</i> gene was 21.4% (3/14), which is significantly higher than the 15.0% observed in the fair-skinned WS2 population. Our results indicate that <i>MITF</i> mutations are relatively common among Chinese WS2 patients.</p></div

The KCNJ10 c.812G>A mutation identified in Chinese patients with nonsyndromic enlargement of vestibular aqueduct (NSEVA).

<p>wt, wild-type; P, father of proband (paternal); M, mother of proband (maternal).</p><p>The KCNJ10 c.812G>A mutation identified in Chinese patients with nonsyndromic enlargement of vestibular aqueduct (NSEVA).</p