Nonsyndromic Hearing Loss Family Research Articles

Identification of a novel mutation of CEACAM16 gene in a Chinese family with autosomal dominant nonsyndromic hearing loss

Objective:To explore the genetic cause of a Chinese autosomal dominant nonsyndromic hearing loss family and investigate the clinical features and molecular genetic characteristics of this family. Method:Detailed medical history and systematic audiology tests were carried out in the family members, and they were subjected to comprehensive genetic analyses using massively parallel sequencing, which targeted 139 known deafness genes and 6 mitochondrial DNA mutations associated with hearing loss. Result:This family's hearing loss was consistent with autosomal dominant nonsyndromic hearing loss. The affected family members appeared to have developed a high-frequency hearing loss with the onset of twenties. We identified a heterozygous missense mutation, c.418A>G/p. Thr140Ala in the CEACAM16 gene, segregating with the deafness in this family. Conclusion:In this study, we identified a new mutation of CEACAM16 gene, which was the second mutation identified in Chinese hearing loss population. It has enriched the mutation spectrum of this gene.

Mutation analysis and early pregnancy prenatal diagnosis for two families affected with non-syndromic hearing loss

Objective:The aim of this study is to identify the pathogenic genes of two non-syndromic hearing loss families, provide accurate genetic counseling and early pregnancy prenatal diagnosis services for second birth families, which determine the genotype of the fetus, early diagnosis and early intervention to prevent the birth of deaf children. Method:Two families with a severe sensorineural hearing loss were enrolled in this study. Genomic DNA was extracted from the peripheral venous blood of the proband and parents. The mutations of the four hearing loss susceptibility genes were analyzed by the hereditary hearing loss gene detection kit (PCR reverse hybridization) and Sanger sequencing. After confirming the genotype of the subject, the genotype of the fetus was examined for the fetus with 10 to 12 weeks of gestation, and the neonates were diagnosed with prenatal diagnosis. Result:In the two families, the No. 1 family proband was the compound heterozygous mutation of SLC26A4 gene c.IVS72A＞G/c.2177insCTAT, and parents were carriers. The prenatal diagnosis showed that the fetal genotype of No. 1 family was a compound heterozygous mutation, and the fetus was not born. The No. 2 family proband genotype was the compound heterozygous of GJB2 gene c.605ins46/c.512insAACG, and the parents were both carriers. The No. 2 family, the prenatal diagnosis showed the fetal genotype of No. 2 family GJB2 gene sequence was normal, the newborn passed the hearing screening. Conclusion:Genetic testing of hereditary hearing loss combined with prenatal diagnosis plays a significant role in guiding deaf children with re-fertility needs, especially prenatal diagnosis in early pregnancy, which can achieve early diagnosis, early detection and early intervention, effectively reducing the birth rate of children with deafness.

A clinical guidance to DFNA22 drawn from a Korean cohort study with an autosomal dominant deaf population: A retrospective cohort study.

The MYO6 gene, if altered, can cause nonsyndromic hearing loss (NSHL) either in an autosomal dominant (AD) (DFNA22) or recessive form. The present study identified MYO6 variants in the cohort of Korean AD NSHL families and investigated the audiological phenotypes of DFNA22 with respect to suggesting clinical guides for the counseling of DFNA22. A retrospective cohort study was performed on 81AD NSHL families in two hospitals. Among them, five families (SH21, SB60, SB247, SB290 and SB305) segregating with MYO6 variant were genetically and clinically assessed. We identified two novel missense variants of MYO6: p.G223R (SB290) and p.T158R (SB305). A known heterozygous truncation variant, p.R205X, reported previously (SH21, SB60), was identified (SB247). The overall frequency of DFNA22 among such cases was 6.2%. Specifically, we found p.R205X from three of five DFNA22 families (60%). Five DFNA22 families demonstrated extremely diverse audiogram configurations and age of onset with even intrafamilial variations, whereas the severity of hearing loss mostly ranged within moderate. We report a recurring predominant allele and two new missense variants of MYO6, highlighting the significant contribution of MYO6 to AD NSHL in the Korean population. Extremely diverse audiological configurations of DFNA22 suggest that MYO6 should be considered in future genetic studies of patients with AD NSHL. Gradual progression with a good speech audiometry score could provide physicians with clinical insight with respect to advising patients to use hearing aids or consider middle ear implants, whereas, in the case of certain exceptional circumstances, physicians could provide patients with the option to consider a cochlear implant.

Novel mutation located in EC7 domain of protocadherin-15 uncovered by targeted massively parallel sequencing in a family segregating non-syndromic deafness DFNB23

ObjectiveHereditary hearing loss is a clinically and genetically heterogeneous disorder associated with mutations of a large number of diverse genes. In this study we applied targeted capture and massively parallel sequencing to identify the disease-causing gene of a Chinese family segregating recessive inherited deafness. MethodsAfter excluding mutations in common deafness genes GJB2, SLC26A4, mitochondrial m.1555A>G, genomic DNA of the proband of family GDSW24 was subjected to targeted next-generation sequencing. Subsequently, a candidate homozygous mutation was confirmed by Sanger sequencing. ResultsA novel PCDH15 c.2367_2369delTGT/p.V788-homozygous mutation was detected. In this family, no obvious vestibular disorder was found. The in-frame mutation c.2367_2369delTGT is located in the evolutionarily conserved EC7 domain of Protocadherin-15 and was predicted to be pathogenic. ConclusionThe novel homozygous mutation in a family segregating non-syndromic hearing loss family supports previous reported observations that PCDH15 does not only causes Usher syndrome type 1F, but also DFNB23.

Analysis and prenatal diagnosis of deafness-related gene mutations in patients with nonsyndromic hearing loss

To analyze deaf-related genes in patients with nonsyndromic hearing loss (NSHL) and set up a prenatal diagnosis system for such patients. Nine NSHL families were collected. Potential mutations of GJB2 (35delG, 176del16, 235delC, 299delAT), SLC26A4 (2168A> G, IVS7-2A> G), GJB3 (538C> T) and mtDNA (1494C> T, 12S rRNA 1555A> G) were detected by direct sequencing. Maternal blood contamination was excluded prior to the testing. Sixteen patients from 4 families were detected with GJB2 mutations, 8 patients from 2 families were found with SLC26A4 mutations, and 4 patients from 2 families were found with mutations in mtDNA. For 2 patients from one remaining family, no mutations were found with above genes. A diagnostic system for NSHL has been established, which may provide a basis for prenatal diagnosis and genetic counseling to NSHL families.

Multiphasic analysis of whole exome sequencing data identifies a novel mutation of ACTG1 in a nonsyndromic hearing loss family

BackgroundThe genetic heterogeneity of sensorineural hearing loss is a major hurdle to the efficient discovery of disease-causing genes. We designed a multiphasic analysis of copy number variation (CNV), linkage, and single nucleotide variation (SNV) of whole exome sequencing (WES) data for the efficient discovery of mutations causing nonsyndromic hearing loss (NSHL).ResultsFrom WES data, we identified five distinct CNV loci from a NSHL family, but they were not co-segregated among patients. Linkage analysis based on SNVs identified six candidate loci (logarithm of odds [LOD] >1.5). We selected 15 SNVs that co-segregated with NSHL in the family, which were located in six linkage candidate loci. Finally, the novel variant p.M305T in ACTG1 (DFNA20/26) was selected as a disease-causing variant.ConclusionsHere, we present a multiphasic CNV, linkage, and SNV analysis of WES data for the identification of a candidate mutation causing NSHL. Our stepwise, multiphasic approach enabled us to expedite the discovery of disease-causing variants from a large number of patient variants.

Clue to a New Deafness Gene: A Large Chinese Nonsyndromic Hearing Loss Family Linked to DFNA4

Hereditary hearing loss is one of the most common neurosensory defects in humans. Approximately 70% of cases are nonsyndromic and could be inherited in autosomal dominant, autosomal recessive, mitochondrial, X-linked, and Y-linked manners (Wang et al., 2004; Alford, 2011). The autosomal dominant type, comprising 15%–20% of nonsyndromic hearing loss, is monogenic and genetically heterogeneous. Since the first dominant deafness locus (DFNA1) was identified in 1992, a total of 64 DFNA loci have been mapped (DFNA1–DFNA64), and 27 corresponding genes have been identified (http://hereditaryhearingloss.org). Previous studies have revealed that one deafness locus can be linked to more than one gene (Bayazit and Yilmaz, 2006), and the question “one locus, how many genes?” was first raised about a decade ago (Van-Hauwe et al., 1999). So far, several loci, including DFNA2 and DFNA3, have been shown to be related to one or more genes, showing high genetic heterogeneity in hereditary hearing loss (Grifa et al., 1999; Goldstein and Lalwani, 2002; Yan et al., 2011).

Characterization of two Chinese families with aminoglycoside-induced and nonsyndromic hearing loss both carrying a mitochondrial 12S rRNA 1494C>T mutation

To evaluate the effect of mitochondrial DNA(mtDNA) secondary mutations, haplotypes, GJB2 gene mutations on phenotype of 1494C>T mutation, and to study the molecular pathogenic mechanism of maternally transmitted aminoglycoside-induced and nonsyndromic hearing loss. Two Chinese Han pedigrees of maternally transmitted aminoglycoside induced and nonsyndromic hearing loss were collected. The two probands and their family members underwent clinical, genetic and molecular evaluations including audiological examinations and mutational analysis of mitochondrial genome and GJB2 gene. Clinical evaluation revealed wide range of severity, age-at-onset and audiometric configuration of hearing impairment in matrilineal relatives in both families, for which the penetrance of hearing loss was respectively 42.9% and 28.6% when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss were 14.3% and 14.3%. Sequence analysis of mitochondrial genomes identified a known 12S rRNA 1494C>T mutation, in addition with distinct sets of mtDNA polymorphisms belonging to Eastern Asian haplogroups C4a1a and B4b1c, respectively. Mitochondrial 12S rRNA 1494C>T mutation probably underlie the deafness in both families. Lack of significant mutation in the GJB2 gene ruled out involvement of GJB2 in the phenotypic expression. However, aminoglycosides and other nuclear modifier genes may still modify the phenotype of the 1494C>T mutation in these families. The B4b1c is a newly identified haplogroup in aminoglycoside-induced and nonsyndromic hearing loss family carrying the 1494C>T mutation. The 1494C>T mutation seems to have occurred sporadically through evolution.

Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology

Hearing loss is a common communication disorder caused by various environmental and genetic factors. Hereditary hearing loss is very heterogeneous, and most of such cases involve sensorineural defects in the auditory pathway. There are currently 57 known autosomal dominant non-syndromic hearing loss (DFNA) loci, and the causative genes have been identified at 22 of these loci. In the present study, we performed a genome-wide linkage analysis in a Korean family segregating autosomal dominant hearing loss. We observed linkage on chromosome 1p34, and at this locus, we detected a novel mutation consisting of an 18 nucleotide deletion in exon 4 of the KCNQ4 gene, which encodes a voltage-gated potassium channel. We carried out a functional in vitro study to analyze the effects of this mutation (c.664_681del) along with two previously described KCNQ4 mutations, p.W276S and p.G285C. Although the c.664_681del mutation is located in the intercellular loop and the two previously described mutations, p.W276S and p.G285C, are located in the pore region, all mutants inhibit normal channel function by a dominant negative effect. Our analysis indicates that the intercellular loop is as significant as the pore region as a potential site of pathogenic effects on KCNQ4 channel function.

Mitochondrial DNA A1555G mutation of seven families with nonsyndromic hearing loss

To study mitochondrial DNA (mtDNA) A1555G mutation in seven families with nonsyndromic hearing loss (NSHL). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real time-amplification refractory mutation system-quantitative PCR (ARMS-qPCR) were applied to detect mtDNA A1555G mutation in seven NSHL families. Related clinical data were also collected and analyzed. The mtDNA A1555G mutation was detected in members from the maternal side, including heteroplasmy and homozygosis, others were negative for this mutation. The copy number of homoplasmic or heteroplasmic mutations of mtDNA A1555G correlated well with the degree of deafness (R = 0.341, P = 0.022 and R = 0.85, P = 0.015, respectively). The mutation rate of the mtDNA A1555G is high in the NSHL patients, the mutation type include heteroplasmy and homozygosis. There is significant correlation between the mtDNA A1555G copy number and the severity of hearing loss.

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele

Introduction: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in...

Human Connexin 30 (GJB6), a Candidate Gene for Nonsyndromic Hearing Loss: Molecular Cloning, Tissue-Specific Expression, and Assignment to Chromosome 13q12

Mutations in connexin 26 are responsible for approximately 20% of genetic hearing loss and 10% of all childhood hearing loss. However, only about 75% of the mutations predicted to be in Cx26 are actually observed. While this may be due to mutations in noncoding regulatory regions, an alternative hypothesis is that some cases may be due to mutations in another gene immediately adjacent to Cx26. Another gap junction gene, connexin 30 (HGMW-approved symbol GJB6), is found to lie on the same PAC clone that hybridizes to chromosome 13q12. Human connexin 26 and connexin 30 are expressed in the same cells of the cochlea. Cx26 and Cx30 share 77% identity in amino acid sequence but Cx30 has an additional 37 amino acids at its C-terminus. These considerations led us to hypothesize that mutations in Cx30 might also be responsible for hearing loss. Eight-eight recessive nonsyndromic hearing loss families from both American and Japanese populations were screened for mutations. In addition, 23 dominant hearing loss families and 6 singleton families presumed to be recessive were tested. No significant mutation has been found in the dominant or recessive families.