UNASSIGNED: Hearing loss is one of the most prevalent congenital sensory disorders. Over 50% of congenital hearing loss cases are attributed to genetic factors. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q, which plays an important role in maintaining the structure and function of the stereocilia of hair cells. Variants in the PTPRQ gene have been implicated in hereditary sensorineural hearing loss.
UNASSIGNED: Utilizing next-generation sequencing technology, we identified novel compound heterozygous variants (c.977G>A:p.W326X and c.6742C>T:p.Q2248X) in the PTPRQ gene within a Chinese national lineage, marking the first association of these variants with hereditary sensorineural hearing loss.
UNASSIGNED: Our findings further emphasize the critical role of PTPRQ in auditory function and contribute to a more comprehensive understanding of PTPRQ-associated hearing loss mechanisms, aiding in clinical management and genetic counseling.

BACKGROUND: This study aims to analyze the pathogenic gene in a Chinese family with non-syndromic hearing loss and identify a novel mutation site in the TNC gene.
METHODS: A five-generation Chinese family from Anhui Province, presenting with autosomal dominant non-syndromic hearing loss, was recruited for this study. By analyzing the family history, conducting clinical examinations, and performing genetic analysis, we have thoroughly investigated potential pathogenic factors in this family. The peripheral blood samples were obtained from 20 family members, and the pathogenic genes were identified through whole exome sequencing. Subsequently, the mutation of gene locus was confirmed using Sanger sequencing. The conservation of TNC mutation sites was assessed using Clustal Omega software. We utilized functional prediction software including dbscSNV_AdaBoost, dbscSNV_RandomForest, NNSplice, NetGene2, and Mutation Taster to accurately predict the pathogenicity of these mutations. Furthermore, exon deletions were validated through RT-PCR analysis.
RESULTS: The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic hearing loss. A novel synonymous variant (c.5247A > T, p.Gly1749Gly) in TNC was identified in affected members. This variant is situated at the exon-intron junction boundary towards the end of exon 18. Notably, glycine residue at position 1749 is highly conserved across various species. Bioinformatics analysis indicates that this synonymous mutation leads to the disruption of the 5\' end donor splicing site in the 18th intron of the TNC gene. Meanwhile, verification experiments have demonstrated that this synonymous mutation disrupts the splicing process of exon 18, leading to complete exon 18 skipping and direct splicing between exons 17 and 19.
CONCLUSIONS: This novel splice-altering variant (c.5247A > T, p.Gly1749Gly) in exon 18 of the TNC gene disrupts normal gene splicing and causes hearing loss among HBD families.

Background: Mutations in the MYO6 gene have been associated with both autosomal dominant non-syndromic hearing loss (ADNSHL) and autosomal recessive non-syndromic hearing loss (ARNSHL), with a cumulative identification of 125 pathogenic variants. To investigate the underlying genetic factor within a Chinese family affected with heriditary hearing loss, prompted the utilization of high-throughput sequencing. Method: A detailed clinical investigation was performed. Genetic testing was performed by using target panel sequencing, and Sanger sequencing. Targeted sequencing identified the variants and Sanger sequencing was employed to validate segregation of the identified variants within family. Additionally, bioinformatics analysis was performed to strengthen our findings. Results: Clinical investigation revealed the family members were affected by progressive and sensorineural hearing loss with an onset around 8-10 years old. Furthermore, genetic testing identified novel MYO6 variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn], positioned in a cis pattern, as plausible pathogenic contributors to early-onset hearing loss characterized by a severe and progressive course. Moreover, bioinformatics analysis showd disruptin in hydrogen bonding of mutant amino acids with interactive amino acids. Conclusion: Our research uncovered a relationship between mutations in the MYO6 gene and non-syndromic hearing loss. We identified two variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn] in MYO6 as strong candidates responsible for the observed progressive hereditary hearing loss. This study not only adds to our knowledge about hearing problems related to MYO6 but also reveals the presence of monogenic compound heterozygosity. Our study will provide a new sight for genetic diagnosis in such patients and their management for future use.

Hereditary hearing loss is a highly heterogeneous disorder. This study aimed to identify the genetic cause of a Chinese family with autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL).
Clinical information and peripheral blood samples were collected from the proband and its parents. Two-step high-throughput next-generation sequencing on the Ion Torrent platform was applied to detect variants as follows. First, long-range PCR was performed to amplify all the regions of the GJB2, GJB3, SLC26A4, and MT-RNR1 genes, followed by next-generation sequencing. If no candidate pathogenetic variants were found, the targeted exon sequencing with AmpliSeq technology was employed to examine another 64 deafness-associated genes. Sanger sequencing was used to identify variants and the lineage co-segregation. The splicing of the MYO15A gene was assessed by in silico bioinformatics prediction and minigene assays.
Two candidate MYO15A gene (OMIM, #602,666) heterozygous splicing variants, NG_011634.2 (NM_016239.3): c.6177 + 1G > T and c.9690 + 1G > A, were identified in the proband, and these two variants were both annotated as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Further bioinformatic analysis predicted that the c.6177 + 1G > T variant might cause exon skipping and that the c.9690 + 1G > A variant might activate a cryptic splicing donor site in the downstream intronic region. An in vitro minigene assay confirmed the above predictions.
We identified a compound heterozygous splicing variant in the MYO15A gene in a Han Chinese family with ARNSHL. Our results broaden the spectrum of MYO15A variants, potentially benefiting the early diagnosis, prevention, and treatment of the disease.

OBJECTIVE: The molecular etiology of non-syndromic hearing loss (NSHL) in Southeastern China (Fujian) has not been precisely identified. our study selected patients with NSHL and analyzed their causative genes, which helped to improve the accuracy of the diagnosis of hereditary hearing loss (HHL) and its treatment.
METHODS: 251 unrelated patients who attended the otolaryngology clinic of Fujian Maternal and Child Health Hospital with hearing loss were enrolled to our study. All patients had genetic tests and listening tests, of which 251 were diagnosed with NSHL. In addition, we used whole-exome sequencing (WES) in a patient who has a significant family history of HHL but negative for gene chip testing, as well as in his family members.
RESULTS: Among of 251 patients, Nucleotide changes were found in 63 cases (25.09%), including 34 located in GJB2(13.5%, including 235delC and 299_300delAT), 13 located in SLC26A4(5.18%, including c.919-2G > A and 2168 A > G), 1 located in GJB3(0.4%,538C > T) and 16 located in mtDNA12SrRNA (6.37%,1555 A > G). In addition, we discuss the process of identifying novel PLS1 mutations from 251 patients.
CONCLUSIONS: Our results demonstrate the conventional deafness gene mutation in 251 NSHL patients in Fujian, China. Compared with the other area of China, we have a lower detection rate, but GJB2 235delC remains the most common mutation in Fujian. In addition, we discuss the process of discovering novel mutation locus for deafness, which provides an understanding for deafness diagnosis and genetic testing.

BACKGROUND: Variants in the MYO7A gene commonly result in Usher syndrome, and in rare cases lead to autosomal dominant non-syndromic deafness (DFNA11). Currently, only nine variants have been reported to be responsible for DFNA11 and their clinical phenotypes are not identical. Here we present a novel variant causing DFNA11 identified in a three-generation Chinese family.
METHODS: The proband was a 53-year-old Han male who presented with post-lingual bilateral symmetrical moderate sensorineural hearing loss. We learned from the patient\'s medical history collection that multiple family members also had similar hearing loss, generally occurring around the age of 40. Subsequent investigation by high-throughput sequencing identified a novel MYO7A variant. To provide evidence supporting that this variant is responsible for the hearing loss in the studied family, we performed Sanger sequencing on 11 family members and found that the variant co-segregated with the deafness phenotype. In addition, the clinical manifestation of the 11 affected family members was found to be late-onset bilateral slowly progressive hearing loss, inherited in this family in an autosomal dominant manner. None of the affected family members had visual impairment or vestibular symptoms; therefore, we believe that this novel MYO7A variant is responsible for the rare DFNA11 in this family.
CONCLUSIONS: We report a novel variant leading to DFNA11 which further enriches the collection of MYO7A variants, and our review of the nine previous variants that have been identified to cause DFNA11 provides a reference for clinical genetic counseling.

UNASSIGNED: Deafness is the most common sensory defect in humans worldwide. Approximately 50% of cases are attributed to genetic factors, and about 70% are non-syndromic hearing loss (NSHL).
UNASSIGNED: To identify clinically relevant gene variants associated with NSHL in a Chinese family using trio-based whole-exome sequencing (WES).
UNASSIGNED: WES was performed on the 18-month-old female proband, and her parents. Gene variants specific to the family were identified by bioinformatics analysis and evaluated for their relevance to NSHL. We verified the novel variant in this family by the next-generation sequencing.In order to elucidate the frameshift mutation of TMPRSS3 in a Chinese family, we used the Mass spectrometry to detect the gene from 1,010 healthy subjects.
UNASSIGNED: We identified a novel homozygous deletion (c.51delA) in exon 2 of the type II transmembrane serine protease 3 gene TMPRSS3, which resulted in a frameshift mutation just before the protein transmembrane domain (p.Q17fs). The deletion was present in the proband and her father, but not in her mother and the healthy controls. We also found mutations with potential relevance to hearing loss in DCAF17, which encodes a protein of unknown function (c. T555A: p.H185Q), and ZNF276, which encodes zinc finger protein 276 (c.1350-2A > G).
UNASSIGNED: We shown a novel frameshift mutation in TMPRSS3 associated with autosomal recessive NSHL in a Han Chinese family.

The frequency of the pathogenic allele of the autosomal recessive deafness gene GJB2 varies among different populations in the world, and accumulates to a sufficiently high frequency in certain population. The purpose of this study is to investigate the origin and evolution of GJB2 pathogenic alleles in Chinese deaf patients. Children with non-syndromic hearing loss, and their parents, from 295 families were recruited. Customized capture probes targeted at 943 single nucleotide polymorphisms (SNPs) related to GJB2 gene were designed for sequencing of genomic DNA in blood samples. Haplotypes carrying pathogenic allele were analyzed through linkage disequilibrium block building, ancestry tracing, and extended haplotype heterozygosity calculation. Two pathogenic GJB2 alleles, c.235delC (18.41%) and c.109G > A (15.57%), were observed in 867 donors. For c.235delC allele, three different core haplotypes with one major haplotype (97.32%) were found, and their core SNPs were 100% conserved. For c.109G > A allele, six different haplotypes with one major haplotype (93.28%) were found and the major c.109G > A allele evolved from a specific ancestral haplotype. Geographical origins of donors carrying GJB2 c.109G > A and c.235delC core haplotypes centered between Qinghai and Neimenggu. GJB2 c.235delC has long-range linkage disequilibrium. No positive selection signature was found for GJB2 c.235delC or c.109G > A in the studied population. In conclusion, we discovered a single origin of GJB2 c.235delC allele and multiple independent origins of GJB2 c.109G > A allele. Alternative to positive selection or multiple independent recurrent mutation event, population bottleneck effect might account for the observed high population frequency of these pathogenic alleles.

Non-syndromic hearing loss (NSHL) is a common neurosensory disease with an extreme genetic heterogeneity which has been linked to variants in over 120 genes. The LOXHD1 gene (DFNB77), encoding lipoxygenase homology domain 1, is a rare hearing loss gene found in several populations. To evaluate the importance of LOXHD1 variants in Chinese patients with NSHL, we performed genetic analysis on LOXHD1 in 2,901 sporadic Chinese patients to identify the aspect and frequency of LOXHD1 causative variants. Next-generation sequencing using a custom gene panel of HL was conducted on 2,641 unrelated patients and whole-exome sequencing on the remaining 260 patients. A total of 33 likely causative variants were identified in 21 patients, including 20 novel variants and 13 previously reported pathogenic variants. Each of the 20 novel variants was evaluated according to ACMG criteria. These findings showed that causative variants in LOXHD1 were found in about 0.72% (21/2,901) of Chinese NSHL patients. This study is by far the largest number of novel variants identified in this gene expanding the range of pathogenic variants in LOXHD1, and suggests that variants in this gene occur relatively commonly in Chinese NSHL patients. This extensive investigation of LOXHD1 in Chinese NSHL patients proposed six recurrent LOXHD1 variants. These findings may assist in both molecular diagnosis and genetic counseling.

Objective:The aim of this study is to analyze the mutation characteristics of GJB2 and SLC26A4 gene in patients with delayed non-syndromic hearing loss, which is beneficial to the early detection and intervention of delayed deafness. Methods:Sanger sequencing technology was used to detect two common genes in 139 patients with non-syndromic deafness, six hot spot mutations in GJB2 gene and SLC26A4 gene, and single heterozygous mutations found in GJB2 gene and SLC26A4 gene were detected by whole exome sequencing. Results:Among the 25 patients with deafness caused by GJB2 gene mutation, 12 of them passed universal newborn hearing screening and then developed delayed extremely severe hearing loss. The onset time of hearing loss was 6-48 months. All the genotypes were homozygous or compound heterozygous mutation of c. 235delC, especially genotype of GJB2 c. 235delC homozygous and c. 235delC/c. 299-300 delAT compound heterozygous mutations, and the CT manifestations were normal. Among the 42 patients with deafness caused by SLC26A4 gene mutation, 30 of them passed universal newborn hearing screening and developed delayed deafness. The onset time of hearing loss was three months to ten years old. Among them, the genotypes of 21 patients were compound heterozygous mutation, and 9 patients were homozygous mutation of c. 919-2A>G, especially genotypes were SLC26A4 c. 919-2A>G/c. 665G>T and c. 919-2A>G /c. 2027T>A compound heterozygous mutation. The CT findings of 19 cases showed single enlarged vestibular aqueduct, and 11 cases showed enlarged vestibular aqueduct with Mondini malformation. Conclusion:For the children who have passed universal newborn hearing screening, the genotypes detected are GJB2 c. 235delC homozygous, SLC26A4 c. 919-2A>G homozygous or compound heterozygous mutations, especially genotypes GJB2 c. 235delC homozygous, c. 235delC/c. 299-300delAT compound heterozygous mutations and SLC26A4 c. 919-2A>G/c. 665G>T and c. 919-2A>G/c. 2027T>A compound heterozygous mutation. Attention should be paid to the hearing problems of children all the time, and the possibility of delayed deafness in the future should be considered.
目的：分析迟发性非综合征性耳聋患者GJB2和SLC26A4基因突变特点，利于迟发性耳聋的早期发现和干预。 方法：应用Sanger测序技术对139例非综合征性耳聋患者的2个常见基因，即GJB2基因和SLC26A4基因的6个热点突变进行检测，对在GJB2基因和SLC26A4基因检测发现的单杂合突变再行全外显子检测。 结果：25例由GJB2基因突变致聋的患者，其中12例患者出生时通过听力筛查后发展为迟发性极重度聋，开始出现听力下降的时间为6~48个月，基因型均为c.235delC纯合或复合杂合突变，尤其基因型为GJB2 c.235delC纯合和c.235delC/ c.299-300delAT复合杂合突变，CT表现正常。42例由SLC26A4基因突变致聋的患者中，30例患者出生时通过了听力筛查，随后发展为迟发性耳聋，开始出现听力下降的时间为3个月~10岁。其中21例基因型为复合杂合突变，9例为c.919-2A>G纯合突变，尤其基因型为SLC26A4 c.919-2A>G/c.665G>T和c.919-2A>G/c.2027T>A复合杂合突变。19例CT表现为单独前庭导水管扩大，11例表现为前庭导水管扩大伴Mondini畸形。 结论：对于出生时通过了听力筛查，同时基因检测的基因型为GJB2 c.235delC纯合、SLC26A4 c.919-2A>G纯合或复合杂合突变，尤其基因型为GJB2 c.235delC纯合和c.235delC/c.299-300delAT复合杂合突变及SLC26A4 c.919-2A>G/c.665G>T和c.919-2A>G/c.2027T>A复合杂合突变者，应时刻关注听力问题，考虑后续有迟发性耳聋的可能。.