Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family

Abstract Background Premature Ovarian Insufficiency plagues 1% of women under 40, while quite a few remain an unknown cause. The development of sequencing has helped find pathogenic genes and reveal the relationship between DNA repair and ovarian reserve. Through the exome sequencing, our study targets screening out the possible POI pathogenic gene and variants in a Chinese family and 20 sporadic POI patients, preliminarily exploring the functional impact and finding out potential linkages between the gene and POI. Results The whole exome sequencing suggested a novel FMN2 heterozygous variant c.1949C > T (p.Ser650Leu) carried by all three patients in a Chinese family and another c.1967G > A(p.Arg656His) variant in a sporadic case. Since no FMN2 missense mutation is reported for causing human POI, we preliminarily assessed p.Ser650Leu variant via cross-species alignment and 3D modeling and found it possibly deleterious. A series of functional evidence was consistent with our hypothesis. We proved the expression of FMN2 in different stages of oocytes and observed a statistical difference of chromosomal breakages between the POI patient carrying p.Arg656His variant and the health control (p = 0.0013). Western Blot also suggested a decrease in FMN2 and P21 in the mutant type and an associated increase in H2AX. The p.Arg656His variant with an extremely low frequency also indicated that the gene FMN2 might play an essential role in the genetic etiology of POI. To the best of our knowledge, this is the first POI report on missense variants of FMN2. Conclusion This finding indicates a novel gene possibly related to POI and sheds lights on the study of FMN2.

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Post-lingual non-syndromic hearing loss phenotype: a novel homozygous missense mutation in MITF

10.21203/rs.2.13328/v2 ◽

2019 ◽

Author(s):

Athar Khalil ◽

Samer Bou Karroum ◽

Rana Barake ◽

Gabriel Dunya ◽

Samer Abou-Rizk ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Missense Mutation ◽

The Novel ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Whole Exome ◽

Genetic Hearing Loss ◽

Syndromic Hearing Loss ◽

And Function

Abstract Background Hearing loss (HL) represents the most common congenital sensory impairment with an incidence of 1-5 per 1000 live births. Non-syndromic hearing loss (NSHL) is an isolated finding that is not part of any other disorder accounting for 70% of all genetic hearing loss cases. Methods In the current study, we report a multifactorial genetic mode of inheritance in a NSHL consanguineous family using exome sequencing technology. We evaluated the possible effects of the single nucleotide variants (SNVs) detected in our patients using in silico methods. Results Two bi-allelic SNVs were detected in the affected patients; a MYO15A (. p.V485A) variant, and a novel MITF (p.P338L) variant. Along with these homozygous mutations, we detected two heterozygous variants in well described hearing loss genes (MYO7A and MYH14). The novel p. Pro338Leu missense mutation on the MITF protein was predicted to change the protein structure and function. Conclusion The novel MITF variant is the first bi-allelic SNV in this gene to be associated with an autosomal recessive non-syndromic HL case with a post-lingual onset. Our findings highlight the importance of whole exome sequencing for a comprehensive assessment of the genetic heterogeneity of HL.

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Missense Variant of Endoplasmic Reticulum Region of WFS1 Gene Causes Autosomal Dominant Hearing Loss without Syndromic Phenotype

BioMed Research International ◽

10.1155/2021/6624744 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Jinying Li ◽

Hongen Xu ◽

Jianfeng Sun ◽

Yongan Tian ◽

Danhua Liu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Hearing Loss ◽

Autosomal Dominant ◽

Low Frequency ◽

Missense Variant ◽

Normal Subjects ◽

Pathogenic Variant ◽

Chinese Family ◽

Missense Variants ◽

Wfs1 Gene

Objective. Genetic variants in the WFS1 gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of WFS1 variants. Methods. The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure. Results. A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the WFS1 gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related WFS1 missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein. Conclusions. In this family, we identified a novel variant p.Gly674Trp of WFS1 as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the WFS1 gene.

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Exome sequencing reveals a novel MFN2 missense mutation in a Chinese family with Charcot‑Marie‑Tooth type 2A

Experimental and Therapeutic Medicine ◽

10.3892/etm.2018.6513 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yi You ◽

Xiaodong Wang ◽

Shan Li ◽

Xiuli Zhao ◽

Xue Zhang

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Chinese Family ◽

Charcot Marie Tooth ◽

Tooth Type

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Whole-exome sequencing identifies a Novel SCN5A mutation (C335R) in a Chinese family with arrhythmia

Cardiology in the Young ◽

10.1017/s1047951117002980 ◽

2018 ◽

Vol 28 (5) ◽

pp. 688-691 ◽

Cited By ~ 2

Author(s):

Hao Huang ◽

Dong-Bo Ding ◽

Liang-Liang Fan ◽

Jie-Yuan Jin ◽

Jing-Jing Li ◽

...

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Chinese Family ◽

Illumina Hiseq ◽

Α Subunit ◽

Pathogenic Genes ◽

Whole Exome ◽

Gene Filtering ◽

Protein Dysfunction

AbstractBackgroundSCN5A encodes sodium-channel α-subunit Nav1.5. The mutations of SCN5A can lead to hereditary cardiac arrhythmias such as the long-QT syndrome type 3 and Brugada syndrome. Here we sought to identify novel mutations in a family with arrhythmia.MethodsGenomic DNA was isolated from blood of the proband, who was diagnosed with atrial flutter. Illumina Hiseq 2000 whole-exome sequencing was performed and an arrhythmia-related gene-filtering strategy was used to analyse the pathogenic genes. Sanger sequencing was applied to verify the mutation co-segregated in the family.Results and conclusionsA novel missense mutation in SCN5A (C335R) was identified, and this mutation co-segregated within the affected family members. This missense mutation was predicted to result in amplitude reduction in peak Na+ current, further leading to channel protein dysfunction. Our study expands the spectrum of SCN5A mutations and contributes to genetic counselling of families with arrhythmia.

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Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

BMC Medical Genomics ◽

10.1186/s12920-021-00871-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Guangxian Yang ◽

Yi Yin ◽

Zhiping Tan ◽

Jian Liu ◽

Xicheng Deng ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Chinese Family ◽

Heterozygous Mutation ◽

Homozygous Mutation ◽

Nonsyndromic Hearing Loss ◽

Whole Exome ◽

Renal Malformations

Abstract Background Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns. Methods A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss. Results Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis. Conclusions This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

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Association of a novel missense mutation in MYO15A with nonsyndromic hearing loss: a case report

10.21203/rs.3.rs-34119/v1 ◽

2020 ◽

Author(s):

Siji Wang ◽

Ziqi Chen ◽

Jiaqiu Dai ◽

Xi Ouyang ◽

Lin Zhu ◽

...

Keyword(s):

Hearing Loss ◽

Missense Mutation ◽

Sanger Sequencing ◽

Three Dimensional ◽

Sensorineural Deafness ◽

Chinese Family ◽

Common Disease ◽

Compound Heterozygous ◽

Nonsyndromic Hearing Loss ◽

Genetic Sequencing

Abstract Background Hearing loss is a common disease globally, and more than 50% of the cases are genetic. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is one of the most common types of hereditary hearing loss. Here, a novel MYO15A missense mutation was identified in a Chinese family with ARNSHL, using targeted genetic sequencing and Sanger sequencing. Case presentation: A 6-year-old girl with congenital nonsyndromic sensorineural deafness was presented from the First Affiliated hospital of Chongqing Medical University, China. We used targeted region sequencing, Sanger sequencing, functional prediction, and three-dimensional protein structure modeling to identify and verify the genes responsible for deafness in the family. Conclusions We found pathogenic compound heterozygous mutations in MYO15A, including a novel missense mutation, c.6353T > C (p.Leu2118Pro). It could provide help not only for genetic counseling but also for further understanding of the functional role of MYO15A mutations.

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