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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 (MITF) gene mutations account for about 15% of WS type II (WS2) cases. To date, fewer than 40 different MITF 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 MITF 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 MITF 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 MITF 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 MITF mutations are relatively common among Chinese WS2 patients. [ABSTRACT FROM AUTHOR]

Hereditary hearing loss is characterized by remarkable phenotypic heterogeneity. Patients with the same pathogenic mutations may exhibit various hearing loss phenotypes. In the Chinese population, the c.235delC mutation is the most common pathogenic mutation of GJB2 and is closely related to hereditary recessive hearing loss. Here, we investigated the hearing phenotypes of patients with hearing loss associated with the homozygous c.235delC mutation, paying special attention to asymmetric interaural hearing loss. A total of 244 patients with the GJB2 c.235delC homozygous mutation encountered from 2007 to 2015 were enrolled. The severity of hearing loss was scaled with the American Speech-Language-Hearing Association (ASHA). Auditory phenotypes were analyzed, and three types of interaural asymmetry were defined based on audiograms: Type A (asymmetry of hearing loss severity), Type B (asymmetry of audiogram shape), and Type C (Type A plus Type B). Of the 488 ears (244 cases) examined, 71.93% (351) presented with profound hearing loss, 14.34% (70) with severe hearing loss, and 9.43% (46) with moderate to severe hearing loss. The most common audiogram shapes were descending (31.15%) and flat (24.18%). A total of 156 (63.93%) of the 244 patients exhibited asymmetric interaural hearing loss in terms of severity and/or audiogram shape. Type A was evident in 14 of these cases, Type B in 106, and Type C in 36. In addition, 211 of 312 ears (67.63%) in the interaural hearing asymmetry group showed profound hearing loss, and 59 (18.91%) exhibited severe hearing loss, with the most common audiogram shapes being flat (27.88%) and descending (22.12%). By contrast, in the interaural hearing symmetry group, profound hearing loss was observed in 140 ears (79.55%), and the most common audiograms were descending (46.59%) and residual (21.59%). Hearing loss associated with the GJB2 c.235delC homozygous mutation shows diverse phenotypes, and a considerable proportion of patients show bilateral hearing loss asymmetry. [ABSTRACT FROM AUTHOR]

Background: Treacher Collins syndrome (TCS) is a clinically and genetically heterogeneous disorder of craniofacial development mainly caused by variants in TCOF1, POLR1D, and POLR1C. Objectives: This study examined the causative genes of five TCS cases. Materials and Methods: In this study, two familial cases and three sporadic cases clinically diagonsed with TCS are described. Mutational analysis in probands was performed by targeted next-generation sequencing (NGS). Mutations identified by NGS were further confirmed by Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). Results: A novel gross deletion (exons 9–13), a novel small deletion (c.381_382delAG), and two known deletions (c.4131_4135delAAAAG and c.2394_2395delAG) within TCOF1 as well as a known mutation (c.91C > T) in POLR1D were identified. These five cases exhibited high inter- and intra-familial phenotypic heterogeneity. Conclusion: This is the first report of Chinese TCS cases caused by a gross deletion within TCOF1 and mutations in POLR1D. In addition to expanding the spectrum of TCS-associated mutation in the Chinese population, our findings present the diversity of its clinical presentation. It is recommended that analyses such as NGS or MLPA capable of detecting large deletions be undertaken as a part of TCS molecular diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Objective Hereditary nonsyndromic hearing loss is extremely heterogeneous and an X-linked form accounts for 1–5% of all cases. The aim of this study was to identify the pathogenic variants in a nonsyndromic X-linked dominant hearing loss family, and explain the reason of different hearing phenotype in hearing between the two sisters with the same variant. Methods Targeted gene capture and next-generation sequencing were used to study the genetic cause. What's more, methylation differences among the androgen receptor genes were used to investigate whether the different hearing levels of the two sisters is related to X-chromosome inactivation (Xi). Results We identified SMPX c.29insA (p.Asn10Lysfs*3) as the novel variant causing deafness. The skewed X-chromosome inactivation was relevant to the hearing difference between the two sisters. Conclusion Targeted gene capture and NGS is an efficient way to identify pathogenic variants in genes. Analysis of X-chromosome inactivation is beneficial to the diagnosis and genetic counseling of X-linked dominant hearing loss families. [ABSTRACT FROM AUTHOR]

Background Mutations in GJB3 were originally shown to underlie an autosomal dominant form of non-syndromic deafness in Chinese patients and the c.538C>T (p.R180*) variants caused high-frequency hearing loss. But after that, few reports have reported this mutation. This study investigated the relationship between the GJB3 c.538C>T variant and hearing phenotype in Chinese to assist with risk assessment and genetic counseling for hearing loss patients and their families. Method The study enrolled 5700 patients with hearing loss and 4600 normal subjects. Deafness gene mutations were distinguished using a gene chip. The GJB3 c.538C>T variant rate was calculated from the results. Result Of the 5700 patients, 23 (0.40%) carried a GJB3 c.538C>T heterozygous variant; of these, 11 patients had other gene ( GJB2 / SLC26A4 ) mutations simultaneously. Most patients had moderate to profound hearing loss. All 23 patients were sporadic cases and had no family history of deafness. Of the 4600 normal individuals, 11 (0.24%) had GJB3 c.538C>T heterozygous variant. There was no statistical difference in incidence between the two groups. Conclusions Our results showed that the GJB3 c.538C>T variant has a very low incidence in the Chinese population, and there was no clear evidence to support a role of the GJB3 c.538C>T variant in the autosomal dominant form of non-syndromic deafness. Our findings suggested that GJB3 c.538C>T does not contribute to hearing loss, and this conclusion will assist with genetic counseling and risk prediction for deafness related to the GJB3 c.538C>T variant. [ABSTRACT FROM AUTHOR]

Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3, one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family. [ABSTRACT FROM AUTHOR]

Background Disease-associated mutations in GJB2 gene are one of the major reasons that can cause non-syndromic sensorineural hearing loss (NSHL). GJB2 gene deafness has various clinical phenotypes. This study aims to analyze characteristics and relationships of clinical phenotypes through analyzing 1481 NSHL cases and 190 GJB2 deafness patients (with dual gene mutations). Patients and methods All the patients diagnosed as deaf disease molecular diagnostics were obtained from the people's liberation army general hospital from March 2007 to March 2011. The accession number of GJB2 was NM_004004 in GenBank, and sequence alignment and annotation were performed using GeneTool software. Results In NSHL patients, mutated allele frequency in GJB2 was 20.57%, and the preponderant type was c.235delC (11.84%) followed by c.109G>A (3.75%). Mutation rate of double allelic gene was 16.18%, including 8.43% of homozygous mutation rate and 7.75% of recombination heterozygosis mutation. Moreover, auditory threshold of GJB2 biallelic marker was associated with ages of onset, while no significant correlation was detected with disease time and whether the inner ear malformation. Similar clinical phenotype could be detected between patients with c.109G>A dual gene mutation and dual gene mutation. However, in the aspect of hearing impairment, the phenomenon of pathopoiesia caused by mutation of c.109G>A was poorer than the other mutations, and even near those patients without pathogenic mutations. Conclusion Our study further shows the definite relationship of clinical phenotype and genotype in GJB2 gene correlated deafness, and these results can provide basis for revealing pathogenesis, gene diagnosis and consult of deafness. The level of evidence in the study is level 4 (case series). [ABSTRACT FROM AUTHOR]

The most common cause of nonsyndromic autosomal recessive hearing loss is mutations in GJB2. The mutation spectrum and prevalence of mutations vary significantly among ethnic groups, and the relationship between p.V37I mutation in GJB2 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 GJB2 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 GJB2 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 GJB2 p.V37I mutation. [ABSTRACT FROM AUTHOR]

Abstract: In most studies, sensorineural hearing loss is reported as a single-gene disease with autosomal dominant or autosomal recessive or with X-linked or maternal inheritance. It is uncommon that the hearing impairment is caused by a combined inheritance model including genomic and mitochondrial models. Here, we report six patients with sensorineural hearing loss caused by co-existing mutations in GJB2 or SLC26A4 and the mitochondrial gene. And there was no significant difference in hearing phenotypes between the six patients and the controls. The results indicate the complicated genetic etiology of, and may impact the diagnostic strategy for, hereditary hearing impairment. All patient siblings will carry mitochondrial DNA A1555G or C1494T mutations, and 25% of siblings may carry the same homozygous or compound heterozygote mutations in GJB2 or SLC26A4. Although this combined inheritance is not common in the Chinese deaf population (0.10%), our findings will have great impact in genetic counseling and risk prediction for deafness. [Copyright &y& Elsevier]

Conclusions: p.R143Q mutation in GJB2 can cause mild to profound bilateral sensorineural hearing impairment. Although not common in Chinese patients with hearing loss, it is important to identify the specific phenotype and genotype correlations of the dominant mutation in GJB2. Objective: Mutations in the GJB2 gene are the most common cause of nonsyndromic autosomal recessive sensorineural hearing loss. A few mutations in GJB2 have also been reported to cause dominant nonsyndromic or syndromic hearing loss. However, dominant mutation in GJB2 is not common in Chinese populations. Methods: Three patients with hearing impairment from Chinese families are reported here. Temporal CT scan, complete physical (including skin and hair) and otoscopic examinations, and an audiological study, including tympanometry, auditory brainstem response (ABR), auditory steady-state response (ASSR), and 40 Hz auditory event-related potential (40 Hz-AERP), were carried out. The two exons of GJB2, the coding exons of S LC26A4, and mitochondrial 12S rRNA were sequenced. Results: Sequencing of GJB2 in two patients showed a heterozygous c.428G>A (p.R143Q) mutation, and the third patient was identified with c.299delAT and c.428G>A compound heterozygous mutation. Sequence analysis of the coding exons of S LC26A4 and mitochondrial 12S rRNA was performed but no sequence aberration or deletion was found. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in mitochondrial DNA (mtDNA) are associated with sensorineural hearing loss. In this study, we traced the origin of the 12S rRNA C1494T mutation through analysis of the clinical, genetic, and molecular characteristics of 13 Han Chinese pedigrees with aminoglycoside-induced and non-syndromic bilateral hearing loss that were selected by C1494T screening in 3133 subjects with non-syndromic hearing impairment from 27 regions of China (13/3133). Clinical evaluation revealed the variable phenotypes of hearing impairment including severity, age-of-onset, and audiometric configuration in these subjects. Through the whole mitochondrial genome DNA sequence analysis, we identified two evolutionarily conservative variants in protein-coding genes: tRNAAla T 5628C and tRNATyr A5836G mutations. However, the pedigrees with these mutations did not have a higher or lower penetrance of deafness than in other pedigrees. These results suggested that both T 5628C and A5836G mutations might not significantly modify the manifestation of the C1494T mutation. Sequencing analysis of the whole mitochondrial genome of the probands showed that 13 pedigrees from seven different provinces were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms, including haplogroups A, B, D, D4, D4b2, F1, M, M7c, N9a1, and H2b. This result suggested that the C1494T mutation occurred sporadically with multi-origins through the evolution of the mtDNA in China, and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. In addition, the lack of a significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. Therefore, the aminoglycosides is solo well-established factor to contribute to the deafness manifestation of the C1494T mutation, and prevention by avoiding the administration of aminoglycosides in individuals carrying C1494T mutation is the most effective way to protect their vulnerability to deafness. [Copyright &y& Elsevier]