Targeted next-generation sequencing in Uyghur families with non-syndromic sensorineural hearing loss.
Ontology highlight
ABSTRACT:
SUBMITTER: Chen Y
PROVIDER: S-EPMC4444116 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Targeted next-generation sequencing in Uyghur families with non-syndromic sensorineural hearing loss.
Chen Ying Y Wang Zhentao Z Wang Zhaoyan Z Chen Dongye D Chai Yongchuan Y Pang Xiuhong X Sun Lianhua L Wang Xiaowen X Yang Tao T Wu Hao H
PloS one 20150526 5
The mutation spectrum of deafness genes may vary in different ethnical groups. In this study, we investigated the genetic etiology of nonsyndromic deafness in four consanguineous and two multiplex Uyghur families in which mutations in common deafness genes GJB2, SLC26A4 and MT-RNR1 were excluded. Targeted next-generation sequencing of 97 deafness genes was performed in the probands of each family. Novel pathogenic mutations were identified in four probands including the p.L416R/p.A438T compound ...[more]
Similar Datasets
Project description:Mitochondrial transfer RNA mutation is one of the most important causes of hereditary hearing loss in humans. Mitochondrial transfer RNASer (UCN) gene is another hot spot for mutations associated with non-syndromic hearing loss, besides the 12S ribosomal RNA gene. In this study, we assessed the clinical phenotype and the molecular characteristics of two Chinese families with non-syndromic hearing loss. Mutational analysis revealed that 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene were the molecular etiology of Family 1 and Family 2, respectively. However, the clinical and genetic characteristics of the two families carrying the above mutations in the transfer RNASer (UCN) gene exhibited a variable expression of hearing loss and an incomplete penetrance. Sequencing analysis of the complete mitochondrial genome showed the presence of transfer RNATrp 5568A > G and NADH-ubiquinone oxidoreductase chain 4 11696G > A mutations in Family 1. The mitochondrial haplotype analysis showed that the two families belonged to Asian D4 and M80'D haplotypes, respectively, and no pathogenic variations were found in the nuclear genes. To our knowledge, our study is the first to report 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene, in multi-generation non-syndromic hearing loss pedigrees from China. Our study suggests that 5568A > G and 11696G > A mutations may enhance the penetrance of hearing loss in Chinese Family 1, while mitochondrial haplotypes and known nuclear genes may not be modifiers for the phenotypic expression of 7445A > G and 7510T > C mutations in these Chinese families.
| S-EPMC10945119 | biostudies-literature
Project description:Conventionally the etiology of congenital Non-Syndromic Hearing Loss has been attributed to mutations in the genes involved in ion homeostasis or the structural compartments of the inner ear. However, this contributes to only a part of the problem, as still the determinants for a large majority of the Non-Syndromic Hearing loss seems to be an enigma. Evidences indicate that pathogens like Rubella, Cytomegalovirus, and many other infections can also result in congenital hearing loss. Additionally, there are variety of factors other than the viral mediators, that can act as stressors to trigger an altered immune response, during the gestational period of the mother. It is also known that non-specific stimulation of the immune system can mimic an infection status. This indicates a strong role for environmental factors toward their contribution to the pathology, possibly by influencing the host immune response. These varieties of known or unknown environmental factors interact with the susceptible variants in immune response genes in defining the threshold for protection or infection in an individual. Considering this background we propose to present this perspective that threshold of the host immune response during the prenatal conditions, in response to environmental stimulus, might be determined by the susceptible variants in immune response genes. This in turn can directly or indirectly influence the genes involved in maintaining the structural components or ion homeostasis, resulting in hearing loss. The threshold of immune response alterations may be heavily dependent on the immunogenetic profile of the mother or the fetus.
| S-EPMC6919260 | biostudies-literature
Project description:Tremendous progress has been made in our understanding of the molecular basis of hearing and hearing loss. Through recent advances, we have begun to understand the fascinating biology of the auditory system and unveiled new molecular mechanisms of hearing impairment. Changes in the diagnostic impact of genetic testing have occurred, as well as exciting developments in therapeutic options. Molecular diagnosis, which is already a reality for several hearing-associated genes, will doubtlessly continue to increase in the near future, both in terms of the number of mutations tested and the spectrum of genes. Genetic analysis for hearing loss is mostly used for diagnosis and treatment, and relatively rarely for reproductive decisions, in contrast to other inherited disorders. Inherited hearing loss, however, is characterized by impressive genetic heterogeneity. An abundance of genes carry a large number of mutations, but specific mutations in a single gene may lead to syndromic or non-syndromic hearing loss. Some mutations predominate in individual ethnic groups. For clinical and laboratory diagnosticians, it is challenging to keep abreast of the unfolding discoveries. This review aims to provide the framework pertinent to diagnosticians and a practical approach to mutation analysis in the hearing impaired.
| S-EPMC1867482 | biostudies-literature
Project description:Background: An early etiological diagnosis of hearing loss positively impacts children's quality of life including language and cognitive development. Even though hearing loss associates with extremely high genetic and allelic heterogeneity, several studies have proven that Next-Generation Sequencing (NGS)-based gene panel testing significantly reduces the time between onset and diagnosis. Methods: In order to assess the clinical utility of our custom NGS GHELP panel, the prevalence of pathogenic single nucleotide variants, indels or copy number variants was assessed by sequencing 171 nuclear and 8 mitochondrial genes in 155 Spanish individuals with hearing loss. Results: A genetic diagnosis of hearing loss was achieved in 34% (52/155) of the individuals (5 out of 52 were syndromic). Among the diagnosed cases, 87% (45/52) and 12% (6/52) associated with autosomal recessive and dominant inheritance patterns respectively; remarkably, 2% (1/52) associated with mitochondrial inheritance pattern. Although the most frequently mutated genes in this cohort were consistent with those described in the literature (GJB2, OTOF or MYO7A), causative variants in less frequent genes such as TMC1, FGF3 or mitCOX1 were also identified. Moreover, 5% of the diagnosed cases (3/52) were associated with pathogenic copy number variants. Conclusion: The clinical utility of NGS panels that allows identification of different types of pathogenic variants-not only single nucleotide variants/indels in both nuclear and mitochondrial genes but also copy number variants-has been demonstrated to reduce the clinical diagnostic odyssey in hearing loss. Thus, clinical implementation of genomic strategies within the regular clinical practice, and, more significantly, within the newborn screening protocols, is warranted.
| S-EPMC10557071 | biostudies-literature
Project description:The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed.
| S-EPMC3219843 | biostudies-literature
Project description:Hereditary hearing impairment is one of the major and common birth defects in Chinese population. Non-syndromic sensorineural hearing loss (NSHL) is the most common types of hereditary hearing impairment. Genotypically and phenotypically NSHL is extremely heterogenous and follow either autosomal dominant or autosomal recessive or X-linked mode of inheritance. Presently, 127 genes have been identified to be associated with both syndromic and (NSHL). Here, we studied a Chinese family with moderate and profound hearing impairment. The proband is a 30-year old Chinese man. The proband was born with normal hearing and at the age of 5-years, the proband was first noticed with hearing impairment. Gradually and progressively the proband was presented with loss of hearing in his both right and left ears at the age of 30 years. The clinical symptoms, age of onset or progression to loss of hearing was similar in both the proband and his younger brother. The proband's parents are phenotypically normal and non-consanguineous. Clinical diagnosis of the proband and his younger brother has been done by classical pure tone audiogram (PTA). Computed Tomography (CT) found no abnormality in bilateral external ear, middle ear and inner ear. Targeted next generation sequencing was performed with a panel of 127 genes reported to be associated with hereditary hearing impairment. A novel homozygous single nucleotide deletion (c.427delT) in exon 4 of ILDR1 gene has been identified in proband and in his younger brother. Sanger sequencing confirmed that proband's father and mother are carrying this mutation in a heterozygous manner. This mutation has not been identified in 100 normal healthy control individuals. This mutation (c.427delT) causes frameshift (p.Tyr143Ilefs∗19) which leads to the formation of a truncated ILDR1 protein of 162 amino acids instead of the wild type ILDR1 protein of 546 amino acids. ILDR1 associated hereditary hearing impairment is very rare and this is the first report of identifying a loss-of-function mutation in ILDR1 gene associated with hereditary hearing impairment in Chinese population. Our present study also emphasized the significance of rapid, accurate and cost-effective screening for the patient with hereditary hearing impairment by targeted next generation sequencing.
| S-EPMC6370629 | biostudies-literature
Project description:ObjectiveTo investigate immune-related genetic background in bilateral sudden sensorineural hearing loss (SSNHL).Case report and methodsThe case is a 45-year-old man presenting with a 7-year history of bilateral profound SSNHL. Blood biochemical testing demonstrated increased levels of total cholesterol (5.88 mmol/L). Tests for hepatitis B showed a positive antibody against the hepatitis B core antigen. Complement C3 was below the normal value, and complement C4 and IgG were in the lower range of normal values. CT images showed a normal inner ear and vestibular aqueduct but round window membranous ossification on both sides. A total number of 232 immune-associated genes were sequenced using the next generation sequencing technique.ResultsMutations were detected in 5 genes, including the phosphoinositide 3-kinase catalytic subunit delta (PIK3CD), caspase recruitment domain-containing protein 9 (CARD9), complement factor H-related (CFHR2), immunoglobulin lambda-like polypeptide 1 Protein (IGLL1), and transmembrane channel-like gene family 8 (TMC8). In the PIK3CD gene, a C896T substitute in exon 7 was detected. This mutation causes primary immunodeficiency and is an autosomal dominant disease.ConclusionThe PIK3CD C896T mutation responsible for primary immunodeficiency may contribute to the onset of bilateral SSNHL with subsequent rapid progression.
| S-EPMC6002587 | biostudies-literature
Project description:The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
| S-EPMC7709052 | biostudies-literature
Project description:Background and aimsConcurrent hearing and genetic screening of newborns have been widely adopted as an effective strategy in early diagnosis and intervention for hearing loss in many cities in China. Here, we aimed to firstly explore the efficacy of combining conventional hearing screening with genetic screening among the large-scale newborns in Jiangxi Province.MethodsA total of 24,349 newborns from Jiangxi Maternal and Child Health Hospital were enrolled in our study from April 2021 to June 2022. Newborn hearing screening was conducted using otoacoustic emission (OAE) and automated auditory brainstem response (AABR). Meanwhile, newborn dried blood spots were collected and twenty common variants in four genes, including GJB2, SLC26A4, MT-RNR1(12SrRNA), and GJB3, were screened using a BGISEQ-500 next generation sequencing platform. Whole coding regions sequencing of GJB2 and SLC26A4 were performed by Sanger sequencing and NGS, respectively. Following up of hearing for the newborns was undertaken by phone interviews.ResultsAmong the 24,349 newborns, 7.00% (1,704/24,349) were bilaterally or unilaterally referred in their initial hearing screening, whereas 1.30% (316/24,349) exhibited bilateral or unilateral hearing loss in the repeated screening. Genetic screening revealed that 4.813% (1,172/24,349) of the screened newborns were positive for at least one mutant allele (heterozygote, homozygote, or compound heterozygote in one gene, mtDNA homoplasmy or heteroplasmy and combined variants in different genes). A total of 1,146 individuals were identified with mutant allele in one gene, including 525 of GJB2, 371 of SLC26A4, 189 as homoplasmic or heteroplasmic of MT-RNR1, and 61 of GJB3, indicating that GJB2 and SLC26A4 are the most common endemic deafness-associated genes among newborns in Jiangxi Province. Nineteen newborns were detected with combined heterozygous variants in different genes, with "c.235delC heterozygous and c.919-2A > G heterozygous" as the most prevalent genotype. Additionally, seven newborns were screened as homozygotes or compound heterozygotes responsible for congenital or late-onset prelingual hearing loss, including three cases with GJB2 c.235delC homozygous and one with SLC26A4 c.919-2A > G homozygous variant, one case with compound heterozygous variants for GJB2 and two with compound heterozygous variants for SLC26A4. Coding regions sequencing of GJB2 or SLC26A4 for overall 265 infants revealed that 14 individuals were identified as compound heterozygote with a second pathogenic variant not screened by our genetic panel.ConclusionsHerein our study firstly investigated the efficacy of concurrent hearing screening and genetic screening of common hearing impairment variants among large-scale newborns in Jiangxi Province. Concurrent screening provides a more comprehensive approach for management of congenital or delayed onset prelingual hearing loss and prevention of drug-induced hearing impairment for newborns at risk as well as their maternal relatives. An insight into the molecular epidemiology for hearing loss genes among Jiangxi population will also be beneficial to the genetic counseling and birth defect prevention.
| S-EPMC9659731 | biostudies-literature
Project description:Atrioventricular septal defects (AVSDs) account for approximately 5% of all congenital heart disease (CHD). About half of AVSDs are diagnosed in cases with trisomy 21 (Down's syndrome, DS). However, many AVSDs occur sporadically and manifest as non-syndromic. The pathogenesis is complex and has not yet been fully elucidated. In the present study, we applied two advanced applications of next-generation sequencing (NGS) to explore the genetic variations in families with fetal non-syndromic AVSDs. Our study was mainly divided into two steps: (1) low-pass whole-genome sequencing (WGS) was used to detect the genome-wide copy number variations (CNVs) for included subjects; (2) whole-exome sequencing (WES) was used to detect the gene mutations for the subjects without AVSD-associated CNVs. A total of 17 heterozygous de novo CNVs and 19 heterozygous de novo gene mutations were selected, and 15 candidate genes were involved in these variations. Among these heterozygous de novo variations, most have potential pathogenicity for AVSDs, but the others require further investigation to confirm their pathogenicity. Our study not only shows the genetic diversity and the etiological complexity of AVSDs but also shows the rationality and practicability of this sequential genetic detection and analysis strategy.
| S-EPMC6962893 | biostudies-literature