scholarly journals The mitochondrial COI/tRNASER(UCN) G7444A mutation may be associated with hearing impairment in a Han Chinese family

2017 ◽  
Vol 20 (2) ◽  
pp. 43-49
Author(s):  
Y Ding ◽  
B-H Xia ◽  
Y-S Teng ◽  
G-C Zhuo ◽  
J-H Leng
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Genome ◽  
Age At Onset ◽  
Han Chinese ◽  
Pathogenic Variant ◽  
Chinese Family ◽  
12S Rrna ◽  
Pathogenic Variants ◽  
Functional Variants ◽  
High Penetrance

Abstract Variations in mitochondrial genome have been found to be associated with hearing loss. Of these, the mitochondrial 12S rRNA and tRNASer(UCN) are the hot-spots for pathogenic variants associated with deafness. To understand the putative role of mitochondrial DNA (mtDNA) variants in hearing loss, we recently screened the variants in mitochondrial genomes in patients with deafness from the Hangzhou area of Zhejiang Province, People’s Republic of China (PRC). In this study, we describe a maternally-inherited Han Chinese family with high penetrance of hearing loss, notably, the penetrance of hearing loss in this family were 80.0 and 40.0%, when the aminoglycoside was included or excluded. Three matrilineal relatives in this pedigree exhibited different levels of hearing loss with different age at onset. In addition, sequence analysis of the complete mitochondrial genome showed the presence of the well-known C1494T pathogenic variant in the 12S rRNA gene and the G7444A pathogenic variant in the COI/ tRNASer(UCN). The C1494T anomaly had been reported to be a pathogenic mutation associated with aminoglycoside-induced and nonsyndromic hearing loss (AINHL), while the G7444A was considered as a secondary mutation associated with deafness. However, the lack of functional variants in GJB2 and TRMU genes suggested that nuclear modified genes may not play important roles in deafness expression. Thus, the combination of G7444A and C1494T pathogenic variants in the mitochondrial genome may account for the high penetrance of hearing loss in this Chinese family.

scholarly journals Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Yu Ding ◽  
Jianyong Lang ◽  
Junkun Zhang ◽  
Jianfeng Xu ◽  
Xiaojiang Lin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Age At Onset ◽  
12S Rrna ◽  
Specific Pcr ◽  
Functional Variants ◽  
Sanger Sequence ◽  
Allele Specific ◽  
Mitochondrial 12S Rrna ◽  
Pcr Method ◽  
Allele Specific Pcr

Abstract Mitochondrial 12S rRNA A1555G and C1494T mutations are the major contributors to hearing loss. As patients with these mutations are sensitive to aminoglycosides, mutational screening for 12S rRNA is therefore recommended before the use of aminoglycosides. Most recently, we developed a novel multiplex allele-specific PCR (MAS-PCR) that can be used for detecting A1555G and C1494T mutations. In the present study, we employed this MAS-PCR to screen the 12S rRNA mutations in 500 deaf patients and 300 controls from 5 community hospitals. After PCR and electrophoresis, two patients with A1555G and one patient with C1494T were identified, this was consistent with Sanger sequence results. We further traced the origin of three Chinese pedigrees. Clinical evaluation revealed variable phenotypes of hearing loss including severity, age at onset and audiometric configuration in these patients. Sequence analysis of the mitochondrial genomes from matrilineal relatives suggested the presence of three evolutionarily conserved mutations: tRNACys T5802C, tRNALys A8343G and tRNAThr G15930A, which may result the failure in tRNAs metabolism and lead to mitochondrial dysfunction that was responsible for deafness. However, the lack of any functional variants in GJB2, GJB3, GJB6 and TRMU suggested that nuclear genes may not play active roles in deafness expression. Hence, aminoglycosides and mitochondrial genetic background may contribute to the clinical expression of A1555G/C1494T-induced deafness. Our data indicated that the MAS-PCR was a fast, convenience method for screening the 12S rRNA mutations, which was useful for early detection and prevention of mitochondrial deafness.

Maternally inherited hearing loss is associated with the novel mitochondrial tRNASer(UCN) 7505T>C mutation in a Han Chinese family

2010 ◽  
Vol 100 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Xiaowen Tang ◽  
Ronghua Li ◽  
Jing Zheng ◽  
Qin Cai ◽  
Ting Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Han Chinese ◽  
Chinese Family ◽  
The Novel

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

Whole mitochondrial genome screening in two families with hearing loss: detection of a novel mutation in the 12S rRNA gene

2010 ◽  
Vol 30 (6) ◽  
pp. 405-411 ◽  
Author(s):  
Emna Mkaouar-Rebai ◽  
Nourhene Fendri-Kriaa ◽  
Nacim Louhichi ◽  
Abdelaziz Tlili ◽  
Chahnez Triki ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Genome ◽  
Novel Mutation ◽  
Hot Spot ◽  
12S Rrna ◽  
Rrna Gene ◽  
12S Rrna Gene ◽  
Genome Screening ◽  
Mitochondrial 12S Rrna ◽  
Syndromic Hearing Loss

Sensorineural hearing loss has been described in association with different mitochondrial multisystemic syndromes, often characterized by an important neuromuscular involvement. Until now, mutations in mitochondrial DNA, especially in the 12S rRNA, the tRNASer(UCN) and the tRNALeu(UUR) genes, were implicated in syndromic or non-syndromic hearing loss either as a primary cause or as predisposing factors. In the present study, we performed a whole mitochondrial genome screening in two unrelated Tunisian families with inherited hearing loss. Results showed the presence of a novel mutation in the mitochondrial 12S rRNA gene in the two probands of these two families who belong to two different haplogroups: L3 and H6a1. The m.735A>G mutation affects a conserved nucleotide of the mitochondrial 12S rRNA gene in primates and other species and had a conservation index of 78.5% (11/14). We also detected known polymorphisms and sic novel mitochondrial variants. The present study confirmed that the mitochondrial 12S rRNA gene is a hot spot for mutations associated with hearing impairment.

Unique penetrance of hearing loss in a five-generation Chinese family with the mitochondrial 12S rRNA 1555A > G mutation

2011 ◽  
Vol 131 (9) ◽  
pp. 970-975 ◽  
Author(s):  
Meichao Men ◽  
Lu Jiang ◽  
Honghan Wang ◽  
Yalan Liu ◽  
Zhengmao Hu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Chinese Family ◽  
12S Rrna ◽  
Mitochondrial 12S Rrna

scholarly journals MITF p.Arg217Thr Variant Identified in a Han Chinese Family with Tietz/Waardenburg Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Rong Yu ◽  
Lv Liu ◽  
Ya-Li Li ◽  
Liang-Liang Fan
Keyword(s):  
Hearing Loss ◽  
Genetic Disorders ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Han Chinese ◽  
White Hair ◽  
Chinese Family ◽  
Waardenburg Syndrome ◽  
Genetic Lesion

Waardenburg syndrome (WS) is a group of rare genetic disorders characterized by hearing loss, changes in coloring of hair, skin, and eyes, and alterations in the shape of the face. Tietz syndrome is another rare disorder which presented similar phenotypes to WS. Patients with Tietz/Waardenburg syndrome often present with pale blue eyes, albino skin, and distinctive hair coloring, such as a patch of white hair or hair that prematurely turns gray. At present, more than six candidate genes are responsible for four types of Waardenburg syndrome and Tietz syndrome. This study is aimed at identifying the pathogenic gene variants in a three-generation Han Chinese family with hearing loss, blue-gray iris, albino skin, and white hair. In order to discover the molecular genetic lesion underlying the disease phenotype, whole exome sequencing in the proband, with Tietz/Waardenburg syndrome phenotypes, of a Han Chinese family from HeBei, China, was conducted. A novel heterozygous c.650G>C/p.Arg217Thr variant in melanocyte inducing transcription factor (MITF) was identified. Sanger sequencing further validated that this mutation existed in three affected individuals and absent in healthy family members. Bioinformatics analysis predicted that this mutation was deleterious. Our study further identified the genetic lesion of the family. Simultaneously, our study may also contribute to genetic counseling, embryonic screening of in vitro fertilized embryos, and prenatal genetic diagnosis of patients with Tietz/Waardenburg syndrome, especially for the proband, unmarried and unpregnant women, to reduce familial transmission in this Han Chinese family.

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

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.

scholarly journals Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss

Hereditas ◽  
2020 ◽  
Vol 157 (1) ◽  
Author(s):  
Jing Yu ◽  
Wei Jiang ◽  
Li Cao ◽  
Xiaoxue Na ◽  
Jiyun Yang
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Motor Development ◽  
Sensorineural Hearing ◽  
Chinese Family ◽  
Targeted Next Generation Sequencing ◽  
Gross Motor Development ◽  
Pathogenic Variants ◽  
Perrault Syndrome ◽  
Ear Malformations

AbstractMutations in HARS2 are one of the genetic causes of Perrault syndrome, characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction. Here, we identified two novel putative pathogenic variants of HARS2 in a Chinese family with sensorineural hearing loss including two affected male siblings, c.349G > A (p.Asp117Asn) and c.908 T > C (p.Leu303Pro), through targeted next-generation sequencing methods. The two affected siblings (13 and 11 years old) presented with early-onset, rapidly progressive SNHL. The affected siblings did not have any inner ear malformations or delays in gross motor development. Combined with preexisting clinical reports, Perrault syndrome may be latent in some families with non-syndromic deafness associated with HARS2 mutations. The definitive diagnosis of Perrault syndrome based on clinical features alone is a challenge in sporadic males, and preadolescent females with no signs of POI. Our findings further expanded the existing spectrum of HARS2 variants and Perrault syndrome phenotypes, which will assist in molecular diagnosis and genetic counselling of patients with HARS2 mutations.

A COL4A5 Missense Variant in a Han-Chinese Family with X-linked Alport Syndrome

2019 ◽  
Vol 19 (10) ◽  
pp. 758-765
Author(s):  
Yuan Wu ◽  
Yi Guo ◽  
Jinzhong Yuan ◽  
Hongbo Xu ◽  
Yong Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sanger Sequencing ◽  
Alport Syndrome ◽  
Genetic Defect ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Family ◽  
Chain Gene ◽  
Renal Disorder ◽  
The Family

Background: Alport syndrome (AS) is an inherited familial nephropathy, characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain gene (COL4A5). Objective: The purpose of this research is to detect the genetic defect responsible for renal disorder in a 3-generation Han-Chinese pedigree. Methods: Detailed family history and clinical data of the family members were collected and recorded. Whole exome sequencing (WES) was applied in the proband to screen potential genetic variants, and then Sanger sequencing was used to verify the variant within the family. Two hundred unrelated ethnically matched normal individuals (male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as controls. Results: Three patients (I:1, II:1 and II:2) presented microscopic hematuria and proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD) by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified to co-segregate with the renal disorder in this family. The variant was absent in 200 ethnically matched controls. Conclusion: By conducting WES and Sanger sequencing, a COL4A5 missense variant, c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is possible that this variant is the genetic cause of the disorder in this family. Our study may extend the mutation spectrum of XLAS and may be useful for genetic counseling of this family. Further functional studies associated with genetic deficiency are warranted in the following research.

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