scholarly journals A Novel USH2A Variant in a Patient with Hearing Loss and Prenatal Diagnosis of a Familial Fetus: a Case Report and Literature Review

2020 ◽  
Author(s):  
Cong Zhou ◽  
Yuanyuan Xiao ◽  
Hanbing Xie ◽  
Shanling Liu ◽  
Jing Wang
Keyword(s):  
Hearing Loss ◽  
Prenatal Diagnosis ◽  
Novel Mutation ◽  
Relevant Literature ◽  
Usher Syndrome ◽  
Genetic Diagnosis ◽  
Screening Strategy ◽  
Chinese Patient ◽  
Gene Panel ◽  
Compound Heterozygous

Abstract Background: Usher syndrome (USH) is the most common cause of inherited deaf-blindness. This study aimed to identify pathogenic mutations in a Chinese patient with hearing loss and reviewed the relevant literature.Methods: Genomic DNA obtained from a five-year-old girl with hearing loss was analyzed via the disease-targeted gene panel. Results: We identified the compound heterozygous mutations c.8559-2A>G and c.4749delT in Usher syndrome type 2A (USH2A) gene as the underlying cause of the familial hearing loss; the former variation has been reported in the literature, but not the latter. The parents of the girl were heterozygous carriers. The two variants were pathogenic. Based on these findings, amniotic fluid samples were used for prenatal diagnosis of the couple's fetus, which was found to carry c.4749delT but not c.8559-2A>G variation. During the follow-up period of more than 9 months after the birth of the fetus, it was confirmed that the infant was healthy.Conclusions: We performed genetic diagnosis of Usher syndrome by disease-targeted gene panel and have proven that this method can serve as a rapid, high-throughput, and efficient screening strategy. The novel mutation expands the spectrum of USH2A variants in USH.

scholarly journals A novel USH2A variant in a patient with hearing loss and prenatal diagnosis of a familial fetus: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Cong Zhou ◽  
Yuanyuan Xiao ◽  
Hanbing Xie ◽  
Shanling Liu ◽  
Jing Wang
Keyword(s):  
Hearing Loss ◽  
Prenatal Diagnosis ◽  
Usher Syndrome ◽  
Chinese Patient ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Gene Panels

Abstract Background Usher syndrome (USH) is the most common cause of inherited deaf-blindness. The current study aimed to identify pathogenic variants in a Chinese patient with hearing loss and to report the identification of a novel p.(Phe1583Leufs*10) variant in USH2A, which met the needs of prenatal diagnosis of the patient's mother. Case presentation Genomic DNA obtained from a five-year-old girl with hearing loss was analyzed via the hearing loss-targeted gene panels. We identified the compound heterozygous variants c.8559-2A>G and c.4749delT in Usher syndrome type 2A (USH2A) gene as the underlying cause of the patient; the former variation has been reported in the literature, but not the latter. The parents of the girl were heterozygous carriers. The two variants were classified as pathogenic. Based on these findings, amniotic fluid samples were used for prenatal diagnosis of the couple's fetus, which was found to carry c.4749delT but not c.8559-2A>G variation. During the follow-up period of more than 9 months after the birth of the fetus, it was confirmed that the infant was healthy. Conclusions The results of the present study identified two compound heterozygous USH2A variants in a patient with hearing loss and reported a novel USH2A variant which expands the spectrum of USH2A variants in USH.

scholarly journals Identification of Novel CDH23 Variants Causing Moderate to Profound Progressive Nonsyndromic Hearing Loss

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1474
Author(s):  
Khushnooda Ramzan ◽  
Nouf S. Al-Numair ◽  
Sarah Al-Ageel ◽  
Lina Elbaik ◽  
Nadia Sakati ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phenotypic Variability ◽  
Usher Syndrome ◽  
Three Dimensional ◽  
Homozygosity Mapping ◽  
Dimensional Structure ◽  
Molecular Testing ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
Missense Variants

Mutant alleles of CDH23, a gene that encodes a putative calcium-dependent cell-adhesion glycoprotein with multiple cadherin-like domains, are responsible for both recessive DFNB12 nonsyndromic hearing loss (NSHL) and Usher syndrome 1D (USH1D). The encoded protein cadherin 23 (CDH23) plays a vital role in maintaining normal cochlear and retinal function. The present study’s objective was to elucidate the role of DFNB12 allelic variants of CDH23 in Saudi Arabian patients. Four affected offspring of a consanguineous family with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment. Parallel to this study, we illustrate some possible pitfalls that resulted from unexpected allelic heterogeneity during homozygosity mapping due to identifying a shared homozygous region unrelated to the disease locus. Compound heterozygous missense variants (p.(Asp918Asn); p.(Val1670Asp)) in CDH23 were identified in affected patients by exome sequencing. Both the identified missense variants resulted in a substitution of the conserved residues and evaluation by multiple in silico tools predicted their pathogenicity and variable disruption of CDH23 domains. Three-dimensional structure analysis of human CDH23 confirmed that the residue Asp918 is located at a highly conserved DXD peptide motif and is directly involved in “Ca2+” ion contact. In conclusion, our study identifies pathogenic CDH23 variants responsible for isolated moderate to profound NSHL in Saudi patients and further highlights the associated phenotypic variability with a genotypic hierarchy of CDH23 mutations. The current investigation also supports the application of molecular testing in the clinical diagnosis and genetic counseling of hearing loss.

scholarly journals Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Chunyan Chen ◽  
Jiong Gao ◽  
Qing Lv ◽  
Chen Xu ◽  
Yu Xia ◽  
...  
Keyword(s):  
Structural Changes ◽  
Novel Mutation ◽  
3D Structure ◽  
Brain Magnetic Resonance Imaging ◽  
Chinese Patient ◽  
Molar Tooth ◽  
Compound Heterozygous ◽  
3D Protein Structure ◽  
Molar Tooth Sign ◽  
New Variant

Abstract Background Joubert syndrome (JS) is a group of rare congenital disorders characterized by cerebellar vermis dysplasia, developmental delay, and retina dysfunctions. Herein, we reported a Chinese patient carrying a new variant in the AHI1 gene with mild JS, and the 3D structure of the affected Jouberin protein was also predicted. Case presentation The patient was a 31-year-old male, who presented difficulty at finding toys at the age of 2 years, night blindness from age of 5 years, intention tremor and walking imbalance from 29 years of age. Tubular visual field and retina pigmentation were observed on ophthalmology examinations, as well as molar tooth sign on brain magnetic resonance imaging (MRI). Whole exome sequence revealed two compound heterozygous variants at c.2105C>T (p.T702M) and c.1330A>T (p.I444F) in AHI1 gene. The latter one was a novel mutation. The 3D protein structure was predicted using I-TASSER and PyMOL, showing structural changes from functional β-sheet and α-helix to non-functional D-loop, respectively. Conclusions Mild JS due to novel variants at T702M and I444F in the AHI1 gene was reported. The 3D-structural changes in Jouberin protein might underlie the pathogenesis of JS.

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 A Novel Nonsense Mutation ofPOU4F3Gene Causes Autosomal Dominant Hearing Loss

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Chi Zhang ◽  
Mingming Wang ◽  
Yun Xiao ◽  
Fengguo Zhang ◽  
Yicui Zhou ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Nonsense Mutation ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Stop Codon ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Family ◽  
Nonsyndromic Hearing Loss ◽  
Truncated Protein

POU4F3gene encodes a transcription factor which plays an essential role in the maturation and maintenance of hair cells in cochlea and vestibular system. Several mutations ofPOU4F3have been reported to cause autosomal dominant nonsyndromic hearing loss in recent years. In this study, we describe a pathogenic nonsense mutation located inPOU4F3in a four-generation Chinese family. Target region capture sequencing was performed to search for the candidate mutations from 81 genes related to nonsyndromic hearing loss in this family. A novel nonsense mutation ofPOU4F3, c.337C>T (p.Gln113⁎), was identified in a Chinese family characterized by late-onset progressive nonsyndromic hearing loss. The novel mutation cosegregated with hearing loss in this family and was absent in 200 ethnicity-matched controls. The mutation led to a stop codon and thus a truncated protein with no functional domains remained. Transient transfection and immunofluorescence assay revealed that the subcellular localization of the truncated protein differed markedly from normal protein, which could be the underlying reason for complete loss of its normal function. Here, we report the first nonsense mutation ofPOU4F3associated with progressive hearing loss and explored the possible underlying mechanism. Routine examination ofPOU4F3is necessary for the genetic diagnosis of hereditary hearing loss in the future.

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

2016 ◽  
Vol 149 (3) ◽  
pp. 171-175 ◽  
Author(s):  
Pan-Feng Wu ◽  
Shuai Guo ◽  
Xue-Feng Fan ◽  
Liang-Liang Fan ◽  
Jie-Yuan Jin ◽  
...  
Keyword(s):  
De Novo ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Patient ◽  
Regulatory Sequence ◽  
Preaxial Polydactyly ◽  
Thumb Duplication ◽  
Zone Of Polarizing Activity ◽  
The Right ◽  
Triphalangeal Thumb

Preaxial polydactyly (PPD; OMIM 603596), which is characterized as having supernumerary fingers, is an unusual congenital hand abnormality. Triphalangeal thumb (TPT; OMIM 190600) is identified by an extra phalangeal bone and is often found in association with PPD. When in combination, the disease is referred to as PPD type II (PPD II; OMIM 174500). Previous studies have demonstrated that variations in the zone of polarizing activity regulatory sequence (ZRS; chr7:156,583,796-156,584,569; hg19) region are associated with PPD II. In this study, our patient was diagnosed with PPD II, having bilateral thumb duplication and unilateral TPT (on the right hand). Further investigation of possible causative genes identified a de novo heterozygous ZRS mutation (ZRS 428T>A). This novel mutation was neither found in 200 normal controls nor reported in online databases. Moreover, the bioinformatics program Genomic Evolutionary Rate Profiling (GERP) revealed this site (ZRS428) to be evolutionarily highly conserved, and the 428T>A point mutation was predicted to be deleterious by MutationTaster. In conclusion, the affected individual shows bilateral thumb duplication, but unilateral TPT making this case special. Thus, our findings not only further support the important role of ZRS in limb morphogenesis and expand the spectrum of ZRS mutations, but also emphasize the significance of genetic diagnosis and counseling of families with digit number and identity alterations as well.

Non-ocular Stickler Syndrome With a Novel Mutation in COL11A2 Diagnosed by Massively Parallel Sequencing in Japanese Hearing Loss Patients

2015 ◽  
Vol 124 (1_suppl) ◽  
pp. 111S-117S ◽  
Author(s):  
Yoh-ichiro Iwasa ◽  
Hideaki Moteki ◽  
Mitsuru Hattori ◽  
Ririko Sato ◽  
Shin-ya Nishio ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Clinical Symptoms ◽  
Massively Parallel Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Analysis Data ◽  
Massively Parallel ◽  
Stickler Syndrome ◽  
Parallel Sequencing ◽  
First Case

Objectives: This study aims to document the clinical features of patients with COL11A2 mutations and to describe the usefulness of massively parallel sequencing. Methods: One thousand one hundred twenty (1120) Japanese hearing loss patients from 53 ENT departments nationwide participated in this study. Massively parallel sequencing of 63 genes implicated in hearing loss was performed to identify the genetic causes in the Japanese hearing loss patients. Results: A novel mutation in COL11A2 (c.3937_3948delCCCCCAGGGCCA) was detected in an affected family, and it was segregated in all hearing loss individuals. The clinical findings of this family were compatible with non-ocular Stickler syndrome. Orofacial features of mid-facial hypoplasia and slowly progressive mild to moderate hearing loss were also presented. Audiological examinations showed favorable auditory performance with hearing aid(s). Conclusion: This is the first case report of the genetic diagnosis of a non-ocular Stickler syndrome family in the Japanese population. We suggest that it is important to take both genetic analysis data and clinical symptoms into consideration to make an accurate diagnosis.

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