Identification of causative variants in patients with non-syndromic hearing loss in the Minnan region, China by targeted next-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.

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Development and Validation of a Next-Generation Sequencing Panel for Syndromic and Nonsyndromic Hearing Loss

The Journal of Applied Laboratory Medicine ◽

10.1093/jalm/jfaa021 ◽

2020 ◽

Vol 5 (3) ◽

pp. 467-479 ◽

Cited By ~ 1

Author(s):

Malinda Butz ◽

Amber McDonald ◽

Patrick A Lundquist ◽

Melanie Meyer ◽

Sean Harrington ◽

...

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Copy Number Variants ◽

Analytical Sensitivity ◽

Nonsyndromic Hearing Loss ◽

Next Generation ◽

Single Nucleotide Variants ◽

Small Indels ◽

Syndromic Hearing Loss ◽

Generation Sequencing

Abstract Background Deafness and hearing loss are common conditions that can be seen independently or as part of a syndrome and are often mediated by genetic causes. We sought to develop and validate a hereditary hearing loss panel (HHLP) to detect single nucleotide variants (SNVs), insertions and deletions (indels), and copy number variants (CNVs) in 166 genes related to nonsyndromic and syndromic hearing loss. Methods We developed a custom-capture next-generation sequencing (NGS) reagent to detect all coding regions, ±10 flanking bp, for the 166 genes related to nonsyndromic and syndromic hearing loss. Our validation consisted of testing 52 samples to establish accuracy, reproducibility, and analytical sensitivity. In addition to NGS, supplementary methods, including multiplex ligation-dependent probe amplification, long-range PCR, and Sanger sequencing, were used to ensure coverage of regions that had high complexity or homology. Results We observed 100% positive and negative percentage agreement for detection of SNVs (n = 362), small indels (1–22 bp, n = 25), and CNVs (gains, n = 8; losses, n = 17). Finally, we showed that this assay was able to detect variants with a variant allele frequency ≥20% for SNVs and indels and ≥30% to 35% for CNVs. Conclusions We validated an HHLP that detects SNVs, indels, and CNVs in 166 genes related to syndromic and nonsyndromic hearing loss. The results of this assay can be utilized to confirm a diagnosis of hearing loss and related syndromic disorders associated with known causal genes.

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

Neural Plasticity ◽

10.1155/2020/8872185 ◽

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.

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

Neural Plasticity ◽

10.1155/2020/6350479 ◽

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.

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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

Neural Plasticity ◽

10.1155/2020/8860837 ◽

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.

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