A dominant variant in DMXL2 is linked to nonsyndromic hearing loss.

PURPOSE: To explore the genetic etiology of deafness in a dominant family with late-onset, progressive, nonsyndromic hearing loss. METHODS: Genome-wide linkage analysis was performed for 21 family members. Candidate pathogenic variants were identified by whole-exome sequencing of selected family members and confirmed by Sanger sequencing of all family members. Cochlear expression of Dmxl2 was investigated by reverse-transcription polymerase chain reaction (RT-PCR) and immunostaining of the organ of Corti from mice. RESULTS: The causative gene was mapped to a 9.68-Mb candidate region on chromosome 15q21.2 (maximum logarithm of the odds score = 4.03) that contained no previously described deafness genes. Whole-exome sequencing identified heterozygous c.7250G>A (p.Arg2417His) in DMXL2 as the only candidate pathogenic variant segregating the hearing loss. In mouse cochlea, expression of DMXL2 was restricted to the hair cells and the spiral ganglion neurons. CONCLUSION: Our data indicated that the p.Arg2417His variant in DMXL2 is associated with dominant, nonsyndromic hearing loss and suggested an important role of DMXL2 in inner ear function.Genet Med advance online publication 22 September 2016.

[Analysis of genetic mutation in patients with nonsyndromic hearing loss received cochlear implant].

OBJECTIVE: To investigate the prevalence of mutations of the gap junction protein (GJB) 2 and mitochondria 12SrRNA in patients with nonsyndromic hearing loss who received cochlear implant. METHODS: Genomic DNA was extracted from the peripheral blood samples obtained from 100 Chinese patients who had received cochlear implantation, 96 with prelingual hearing loss and 4 with postlingual hearing loss, all very severe. Sixteen of the 100 patients had the history of application of aminoglycosides, among which 12 were with prelingual hearing loss and 4 with postlingual hearing loss. PCR was performed and the products were sequenced by automated DNA sequencer. RESULTS: GJB2 mutations were detected in 34 of the 100 cochlear implant recipients (34%), all with prelingual hearing loss, among which 27 (27%) had 235delC mutation. Among the 16 patients who had used aminoglycosides, two had the mutation A1555G, and one carried the mitochondrial genetic mutation delT961Cn. CONCLUSION: Mutation of GJB2 gene is the major cause of deafness in cochlear implant recipients, with a high frequency of 235delC mutation. Mitochondria genetic mutation A1555G is the common form of mutation in postlingual deafness with a history of aminoglycoside injection.

[Screening of SLC26A4 (PDS) gene mutation in cochlear implant recipients with inner ear malformation].

OBJECTIVE: To determine the prevalence of SLC26A4 (PDS) gene mutations in cochlear implant recipients with inner ear malformation, and the correlation between SLC26A4 (PDS) gene mutation and inner ear malformation and intra-operative testing of the electrically evoked auditory nerve compound action potentials (ECAP). METHODS: Peripheral blood samples were collected from 48 cochlear implant recipients with temporal bone malformation and 50 healthy controls. Genomic DNA was extracted from the blood; PCR and direct sequencing were used to detect the mutations of SLC26A4 (PDS) gene. During the implantation of artificial cochlea the 48 recipients underwent intraoperative neural response telemetry (NRT) to measure the electrically evoked auditory nerve compound action potentials (ECAP). RESULTS: SLC26A4 (PDS) mutations were detected in 70.3% (26/37) of the patients with enlarged vestibular aqueduct (EVA), and 18.2% (2/11) of the patients with other malformations of inner ear. Fifteen different mutations were identified, 8 of which had never been previously reported. The IVS7-2A>G mutation was the most prevalent mutation of SLC26A4 (PDS) gene, accounting for 45.9% (17/37) in the EVA patients. No association was detected between SLC26A4 mutation and ECAP. CONCLUSION: Mutations in the SLC26A4 (PDS) gene is a major cause of EVA, with IVS7-2A>G as the most common mutation form.

Genetic analysis of a Chinese family with members affected with Usher syndrome type II and Waardenburg syndrome type IV.

AIMS: The purpose of this study was to identify the genetic causes of a family presenting with multiple symptoms overlapping Usher syndrome type II (USH2) and Waardenburg syndrome type IV (WS4). METHODS: Targeted next-generation sequencing including the exon and flanking intron sequences of 79 deafness genes was performed on the proband. Co-segregation of the disease phenotype and the detected variants were confirmed in all family members by PCR amplification and Sanger sequencing. RESULTS: The affected members of this family had two different recessive disorders, USH2 and WS4. By targeted next-generation sequencing, we identified that USH2 was caused by a novel missense mutation, p.V4907D in GPR98; whereas WS4 due to p.V185M in EDNRB. This is the first report of homozygous p.V185M mutation in EDNRB in patient with WS4. CONCLUSION: This study reported a Chinese family with multiple independent and overlapping phenotypes. In condition, molecular level analysis was efficient to identify the causative variant p.V4907D in GPR98 and p.V185M in EDNRB, also was helpful to confirm the clinical diagnosis of USH2 and WS4.

[High prevalence of connexin-26 (GJB2) mutation in cochlear implant recipients].

OBJECTIVE: To determine the prevalence of GJB2 gene mutations in patients undergoing cochlear implantation. METHODS: We enrolled 115 cochlear implant recipients for mutation screening. Genomic DNA was extracted from the blood of all patients, amplified in PCR and analyzed for single strand conformation polymorphism (SSCP) or direct sequencing to detect mutations of GJB2 gene. RESULTS: The result shows that the GJB2 mutations are detected in 36.5% (42/115) of the cochlear implant recipients, and especially 41% (41/100) of the non-syndromic deafness patients, only 1 inner ear malformation patient was detected with GJB2 mutations. This study found 11 different variations in the GJB2 gene. The 235delC mutation was the most prevalent mutation accounting for 18.3% (41/230) in all cochlear implant recipients and 21% (42/200) in non-syndromic deafness group. 187G > T and 230G > A mutations were novel mutation of GJB2 gene in the Chinese population. CONCLUSION: Mutations in the GJB2 gene were a major cause of deafness in cochlear implant recipients, the carrier frequency of 235delC mutation was highest.

Mutation in PCDH15 may modify the phenotypic expression of the 7511T>C mutation in MT-TS1 in a Chinese Han family with maternally inherited nonsyndromic hearing loss.

OBJECTIVES: Mutations in MT-TS1 have been found to be associated with nonsyndromic sensorineural hearing loss (SNHL). PCDH15 codes for protocadherin-15, a member of the cadherin superfamily of calcium-dependent cell-cell adhesion molecules. In this study, we analyzed the correlation of both MT-TS1 and PCDH15 mutations in a Chinese Han family segregating maternally inherited nonsyndromic SNHL. METHODS: We ascertained a Chinese Han family segregating maternally inherited nonsyndromic sensorineural hearing loss. Eight of 10 maternal members in this family exhibited late-onset, progressive hearing impairment. Mutation screening of 79 known deafness genes was performed for the proband by targeted next-generation sequencing. RESULTS: A total of 651 variants were detected in this individual. Among them, a homoplasmic 7511T>C variant in MT-TS1, the mitochondrial tRNA (Ser(UCN)) gene, and a heterozygous p.Asp1010Gly variant in PCDH15 were more likely to be pathogenic. Consistent with the matrilineal inheritance with reduced penetrance, the 7511T>C variant in MT-TS1 was found in all 10 maternal members and an additional heterozygous p.Asp1010Gly variant in PCDH15 cosegregated with the hearing loss in this family. CONCLUSION: Our results suggested that the PCDH15 p.Asp1010Gly variant probably modified the phenotypic expression of the 7511T>C mutation in MT-TS1.

Mutation analysis of seven consanguineous Uyghur families with non-syndromic deafness.

OBJECTIVE: To investigate the genetic causes of consanguineous Uyghur families with nonsyndromic deafness. METHOD: Seven consanguineous Uyghur families with nonsyndromic deafness were recruited in this study and characterized for their audiometric phenotype. Mutation analysis of common deafness genes GJB2, SLC26A4 and MT-RNR1 was performed in all families by direct sequencing. RESULT: Bi-allelic mutations in SLC26A4, including p.N392Y/p.N392Y, p.S57X/p.S57X and p.Q413R/p.L676Q, were detected in three families as the pathogenic causes for the deafness. No mutations were identified in GJB2 and MT-RNR1. CONCLUSION: Mutations in SLC26A4 was the most common causes of the Uyghur consanguineous deaf families.

Clinical characterization of a novel COCH mutation G87V in a Chinese DFNA9 family.

OBJECTIVES: To characterize the clinical features of a Chinese DFNA9 family associated with a novel COCH mutation and to confirm the proposed genotype-phenotype correlation of COCH. METHODS: Mutation screening of 79 deafness genes was performed in the proband by targeted next-generation sequencing. Co-segregation of the disease phenotype and the detected variants was confirmed in all family members by PCR amplification and Sanger sequencing. The progression of hearing impairment in affected family members was followed and the concomitant vestibular dysfunction was verified by the caloric vestibulo-ocular reflex test. RESULTS: A novel COCH mutation p.G87V was identified in the family segregating with late-onset, progressive sensorineural hearing impairment and consistent vestibular dysfunction. CONCLUSION: The p.G87V mutation leads to a very similar phenotype as a previously reported p.G87W mutation of COCH. Our study suggested that the G87 residue is critical for function of COCH and further confirms a previously proposed genotype-phenotype correlation for DFNA9.

[Virtual otoscopy of middle ear structure and pathology].

OBJECTIVE: To assess the value of high-resolution CT data of the temporal bone for the virtual endoscopic (VE) visualization of the ossicular chain and the temporal bone. METHODS: Fifty patients with suspected lesions of middle ear underwent a high-resolution CT of the temporal bone with VE, seventeen patients were subsequently operated. CT examinations of the temporal bone were carried out using spiral equipment and endoscopic 3D processing was carried out on a separate workstation equipped with a flying through program. RESULTS: VE is valuable for the evaluation of ossicular dislocation, disruption and ossicular lysis, morphological anomalies of the malleus, incus, and stapes, as well as for evaluation of normal middle ear structures with high detail. The VE assessment in detecting ossicular disruption of chronic otitis media match the operation exploration perfectly (10 in 11 ears), whereas only 3 in 6 ears of cholesteatoma match the operation exploration. CONCLUSIONS: This image processing method can be used pre-operatively for the individual planning, simulation, and post-operatively for assessment of the position of implants.