scholarly journals Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Pengcheng Xu ◽  
Jun Xu ◽  
Hu Peng ◽  
Tao Yang
Keyword(s):  
Hearing Loss ◽  
Next Generation Sequencing ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Next Generation ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Recessive Mutations ◽  
Compound Heterozygous Mutations ◽  
Generation Sequencing

Genetic hearing loss is a common sensory disorder, and its cause is highly heterogeneous. In this study, by targeted next-generation sequencing of 414 known deafness genes, we identified compound heterozygous mutations p.R34X/p.M413T in TMC1 and p.S3417del/p.R1407T in MYO15A in two recessive Chinese Han deaf families. Intrafamilial cosegregation of the mutations with the hearing phenotype was confirmed in both families by the Sanger sequencing. Auditory features of the affected individuals are consistent with that previously reported for recessive mutations in TMC1 and MYO15A. The two novel mutations identified in this study, p.M413T in TMC1 and p.R1407T in MYO15A, are classified as likely pathogenic according to the guidelines of ACMG. Our study expanded the mutation spectrums of TMC1 and MYO15A and illustrated that genotype-phenotype correlation in combination with next-generation sequencing may improve the accuracy for genetic diagnosis of deafness.

scholarly journals Targeted Next-Generation Sequencing Identified Compound Heterozygous Mutations in MYO15A as the Probable Cause of Nonsyndromic Deafness in a Chinese Han Family

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Longhao Wang ◽  
Lin Zhao ◽  
Hu Peng ◽  
Jun Xu ◽  
Yun Lin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Next Generation Sequencing ◽  
Cochlear Implantation ◽  
Compound Heterozygous ◽  
Next Generation ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Before And After ◽  
Compound Heterozygous Mutations ◽  
Generation Sequencing

Hearing loss is a highly heterogeneous disorder, with more than 60% of congenital cases caused by genetic factors. This study is aimed at identifying the genetic cause of congenital hearing loss in a Chinese Han family. Auditory evaluation before and after cochlear implantation and targeted next-generation sequencing of 140 deafness-related genes were performed for the deaf proband. Compound heterozygous mutations c.3658_3662del (p. E1221Wfs∗23) and c.6177+1G>T were identified in MYO15A as the only candidate pathogenic mutations cosegregated with the hearing loss in this family. These two variants were absent in 200 normal-hearing Chinese Hans and were classified as likely pathogenic and pathogenic, respectively, based on the ACMG guideline. Our study further expanded the mutation spectrum of MYO15A as the c.3658_3662del mutation is novel and confirmed that deaf patients with recessive MYO15A mutations have a good outcome for cochlear implantation.

scholarly journals Clinical and genetic study of twelve Chinese Han families with non-syndromic deafness

2019 ◽  
Author(s):  
Di Wu ◽  
Weiyuan Huang ◽  
Shuo Li ◽  
Jie Zhang ◽  
Xiaohua Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Next Generation Sequencing ◽  
Accurate Diagnosis ◽  
Next Generation ◽  
Phenotype Correlation ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Syndromic Hearing Loss ◽  
Generation Sequencing

Abstract BACKGROUND: Non-syndromic hearing loss is clinically and genetically heterogeneous. In this study, we characterized the clinical features of twelve Chinese Han deaf families in which mutations in common deafness genes GJB2 , SLC26A4 and MT-RNR1 were excluded. RESULTS: Targeted next-generation sequencing of 147 known deafness genes was performed in probands of ten families, while whole-exome sequencing was applied in those of the rest two. Pathogenic mutations in a total of 11 rare deafness genes, OTOF , CDH23 , PCDH15 , PDZD7 , ADGRV1 , KARS , OTOG , GRXCR2 , MYO6 , GRHL2 , and POU3F4 , were identified in all 12 probands, with 17 mutations being novel. Intrafamilial co-segregation of the mutations and the deafness phenotype were confirmed by Sanger sequencing. CONCLUSIONS: Our results expanded the mutation spectrum and genotype-phenotype correlation of non-syndromic hearing loss in Chinese Hans and also emphasized the importance of combining both next-generation sequencing and detailed auditory evaluation to achieve a more accurate diagnosis for non-syndromic hearing loss.

scholarly journals Targeted Next-Generation Sequencing Identifies Separate Causes of Hearing Loss in One Deaf Family and Variable Clinical Manifestations for the p.R161C Mutation in SOX10

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Xiaoyu Yu ◽  
Yun Lin ◽  
Hao Wu
Keyword(s):  
Hearing Loss ◽  
Next Generation Sequencing ◽  
Hypogonadotropic Hypogonadism ◽  
Family Members ◽  
Clinical Manifestations ◽  
Next Generation ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Wide Range ◽  
Generation Sequencing

Hearing loss is the most common sensory deficit in humans. Identifying the genetic cause and genotype-phenotype correlation of hearing loss is sometimes challenging due to extensive clinical and genetic heterogeneity. In this study, we applied targeted next-generation sequencing (NGS) to resolve the genetic etiology of hearing loss in a Chinese Han family with multiple affected family members. Targeted sequencing of 415 deafness-related genes identified the heterozygous c.481C>T (p.R161C) mutation in SOX10 and the homozygous c.235delC (p.L79Cfs∗3) mutation in GJB2 as separate pathogenic mutations in distinct affected family members. The SOX10 c.481C>T (p.R161C) mutation has been previously reported in a Caucasian patient with Kallmann syndrome that features congenital hypogonadotropic hypogonadism with anosmia. In contrast, family members carrying the same p.R161C mutation in this study had variable Waardenburg syndrome-associated phenotypes (hearing loss and/or hair hypopigmentation) without olfactory or reproductive anomalies. Our results highlight the importance of applying comprehensive diagnostic approaches such as NGS in molecular diagnosis of hearing loss and show that the p.R161C mutation in SOX10 may be associated with a wide range of variable clinical manifestations.

scholarly journals High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Athanasia Stoupa ◽  
Ghada Al Hage Chehade ◽  
Rim Chaabane ◽  
Dulanjalee Kariyawasam ◽  
Gabor Szinnai ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Congenital Hypothyroidism ◽  
Diagnostic Yield ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Next Generation ◽  
Hormone Production ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

ObjectiveTo elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).Study designWe studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.ResultsTNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.ConclusionsIn a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.

scholarly journals Positive Impact of Expert Reference Center Validation on Performance of Next-Generation Sequencing for Genetic Diagnosis of Autoinflammatory Diseases

2019 ◽  
Vol 8 (10) ◽  
pp. 1729
Author(s):  
Boursier ◽  
Rittore ◽  
Georgin-Lavialle ◽  
Belot ◽  
Galeotti ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Diagnostic Performance ◽  
Positive Impact ◽  
Genetic Diagnosis ◽  
Autoinflammatory Diseases ◽  
Expert Advice ◽  
Next Generation ◽  
Reference Center ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

Monogenic autoinflammatory diseases (AIDs) are caused by variants in genes that regulate innate immunity. The current diagnostic performance of targeted next-generation sequencing (NGS) for AIDs is low. We assessed whether pre-analytic advice from expert clinicians could help improve NGS performance from our 4 years of experience with the sequencing of a panel of 55 AIDs genes. The study included all patients who underwent routine NGS testing between September 2014 and January 2019 at the laboratory of autoinflammatory diseases (Montpellier, France). Before March 2018, all medical requests for testing were accepted. After this time, we required validation by a reference center before NGS: the positive advice could be obtained after a face-to-face consultation with the patient or presentation of the patient’s case at a multidisciplinary staff meeting. Targeted NGS resulted in an overall 7% genetic confirmation, which is consistent with recent reports. The diagnostic performance before and after implementation of the new pre-requisite increased from 6% to 10% (p = 0.021). Our study demonstrated, for the first time, the beneficial effect of a two-step strategy (clinical expert advice, then genetic testing) for AIDs diagnosis and stressed the possible usefulness of the strategy in anticipation of the development of pan-genomic analyses in routine settings.

scholarly journals Genetic landscape of pediatric movement disorders and management implications

2018 ◽  
Vol 4 (5) ◽  
pp. e265 ◽  
Author(s):  
Dawn Cordeiro ◽  
Garrett Bullivant ◽  
Komudi Siriwardena ◽  
Andrea Evans ◽  
Jeff Kobayashi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Movement Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Genetic Diagnosis ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Generation Sequencing

ObjectiveTo identify underlying genetic causes in patients with pediatric movement disorders by genetic investigations.MethodsAll patients with a movement disorder seen in a single Pediatric Genetic Movement Disorder Clinic were included in this retrospective cohort study. We reviewed electronic patient charts for clinical, neuroimaging, biochemical, and molecular genetic features. DNA samples were used for targeted direct sequencing, targeted next-generation sequencing, or whole exome sequencing.ResultsThere were 51 patients in the Pediatric Genetic Movement Disorder Clinic. Twenty-five patients had dystonia, 27 patients had ataxia, 7 patients had chorea-athetosis, 8 patients had tremor, and 7 patients had hyperkinetic movements. A genetic diagnosis was confirmed in 26 patients, including in 20 patients with ataxia and 6 patients with dystonia. Targeted next-generation sequencing panels confirmed a genetic diagnosis in 9 patients, and whole exome sequencing identified a genetic diagnosis in 14 patients.ConclusionsWe report a genetic diagnosis in 26 (51%) patients with pediatric movement disorders seen in a single Pediatric Genetic Movement Disorder Clinic. A genetic diagnosis provided either disease-specific treatment or effected management in 10 patients with a genetic diagnosis, highlighting the importance of early and specific diagnosis.

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