scholarly journals Case Report: A Chinese Family of Woodhouse-Sakati Syndrome With Diabetes Mellitus, With a Novel Biallelic Deletion Mutation of the DCAF17 Gene

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Zhou ◽  
Ningjie Shi ◽  
Juan Zheng ◽  
Yang Chen ◽  
Siqi Wang ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Stop Codon ◽  
Signs And Symptoms ◽  
Homozygous Deletion ◽  
Chinese Family ◽  
Homozygous Mutation ◽  
Chinese Han ◽  
C Peptide ◽  
Whole Exome ◽  
Peptide Release

Woodhouse–Sakati syndrome (WSS) (OMIM#241080) is a rare multi-system autosomal recessive disease with homozygous mutation of the DCAF17 gene. The main features of WSS include diabetes, hypogonadism, alopecia, deafness, intellectual disability and progressive extrapyramidal syndrome. We identified a WSS family with a novel DCAF17 gene mutation type in China. Two unconsanguineous siblings from the Chinese Han family exhibiting signs and symptoms of Woodhouse-Sakati syndrome were presented for evaluation. Whole-exome sequencing revealed a homozygous deletion NM_025000.4:c.1488_1489delAG in the DCAF17 gene, which resulted in a frameshift mutation that led to stop codon formation. We found that the two patients exhibited low insulin and C-peptide release after glucose stimulation by insulin and C-peptide release tests. These findings indicate that the DCAF17 gene mutation may cause pancreatic β cell functional impairment and contribute to the development of diabetes.

A novel homozygous mutation (1619delC) in GPIIb gene associated with Glanzmann thrombasthenia, the decay of GPIIb-mRNA and the synthesis of a truncated GPIIb unable to form complex with GPIIIa

2005 ◽  
Vol 93 (05) ◽  
pp. 904-909 ◽  
Author(s):  
Gergely Losonczy ◽  
Nurit Rosenberg ◽  
Csongor Kiss ◽  
János Kappelmayer ◽  
György Vereb ◽  
...  
Keyword(s):  
Stop Codon ◽  
Flow Cytometric Analysis ◽  
Surface Expression ◽  
Homozygous Deletion ◽  
Homozygous Mutation ◽  
Truncated Form ◽  
Platelet Surface ◽  
Form Complex ◽  
Glanzmann Thrombasthenia ◽  
Fibrinogen Receptor

SummaryThe absence of agonist-induced platelet aggregation and the lack of fibrinogen receptor (GPIIb/IIIa) on the platelet surface demonstrated that the severe hemorrhagic complications of a child of Romany descent were caused by Glanzmann thrombasthenia. DNA sequencing revealed a novel homozygous deletion of a cytosine (1619delC) in the GPIIb gene causing a frameshift and predicting a novel stop codon at position 533 following 24 altered amino acids. Both parents possessed the same deletion in heterozygous form. The amount of GPIIb mRNA in the patient’s platelets was 0.06% of the amount measured in control platelets. Neither GPIIb nor its truncated form could be detected in the platelets of the patient by Western blotting, while a small amount of GPIIIa was demonstrated. Quantitative flow cytometric analysis showed an elevated number of vitronectin receptors, a component of which is GPIIIa, on the patient’s platelets. The surface expression of vitronectin receptor on thrombasthenic, but not on normal platelets was further increased by activation with thrombin receptor agonist peptide. BHK cells transfected with wild type GPIIIa and mutated GPIIb failed to express any mature GPIIb or pro-GPIIb. Immunoprecipitation with a polyclonal antibody recognizing both GPIIb and GPIIIa recovered a 60 kDa truncated form of GPIIb. This band was absent when immunoprecipitation was carried out with an antibody recognizing GPIIIa, suggesting that the truncated protein, lacking calf-1, calf-2 domains and major part of the thigh domain, is unable to form complex with GPIIIa.

scholarly journals 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

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.

scholarly journals Novel Genetic Findings in a Chinese Family with Axenfeld-Rieger Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Kuanshu Li ◽  
Liu Yang ◽  
Ying Liu ◽  
Ding Lin
Keyword(s):  
Genetic Counseling ◽  
Genetic Analysis ◽  
Gene Mutation ◽  
Genomic Dna ◽  
Gene Mutations ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Homozygous Mutation ◽  
Specific Therapy ◽  
Rieger Syndrome

Purpose. To describe a Chinese family with Axenfeld-Rieger syndrome (ARS) and report our novel genetic findings.Methods. Nine members of the same family underwent complete ophthalmologic examinations and genetic analysis. Genomic DNA was isolated from veinal blood and amplifed using PCR; the products of PCR were sequenced and compared with FOXC1 and PITX2 genes, from which the mutations were found.Results. Through the ophthalmologic examinations, 8 subjects were diagnosed as ARS and 1 subject was normal. A homozygous mutation c.1139_1141dupGCG(p.Gly380_Ala381insGly) and a heterozygous mutation c.1359_1361dupCGG(p.Gly456_Gln457insGly) in FOXC1 were identified in all subjects. The mutation (c.-10-30T>C) was identified in PITX2 in subjects III-1 and III-3.Conclusions.We found novel gene mutations in a Chinese family with ARS, which provides us with a better understanding of the gene mutation spectrum of ARS and the assistance for the genetic counseling and gene-specific therapy in the future.

scholarly journals Novel Homozygous Mutation in PDZD7 Gene in a Family with Nonsyndromic Sensorineural Hearing Loss

2021 ◽  
Author(s):  
Qiang Du ◽  
Qin Sun ◽  
Jinchao Wang ◽  
Weitao Li ◽  
Luo Guo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
High Throughput Sequencing ◽  
Stop Codon ◽  
Clinical Importance ◽  
Sensorineural Hearing ◽  
Chinese Family ◽  
Homozygous Mutation ◽  
Severe Hearing Loss ◽  
Sensory Neural

Abstract Hearing loss is the most common sensory neural disorder in human, and according to WHO estimation, 5.5% (466 million) people worldwide have disabling hearing loss. In this study, a Chinese family with prelingual sensorineural hearing loss was investigated. The affected individuals showed moderately-severe hearing loss at all frequencies. Using target genome enrichment and high-throughput sequencing, a homozygous mutation c.2372delC, p.S791Ffs*17 was identified in PDZD7. The deletion mutation lies in exon 15 of PDZD7 and resultes in a frame shift followed by an early stop codon. Our study expand the mutation spectrum of PDZD7 and strengthens the clinical importance of this gene in patients with moderately-severe hearing loss.

Clinical and Genetic Analysis of a Compound Heterozygous Mutation in the Thyroglobulin Gene in a Chinese Twin Family With Congenital Goiter and Hypothyroidism

2012 ◽  
Vol 15 (1) ◽  
pp. 126-132 ◽  
Author(s):  
Shiguo Liu ◽  
Shasha Zhang ◽  
Wenjie Li ◽  
Aiqing Zhang ◽  
Fengguang Qi ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Congenital Hypothyroidism ◽  
High Performance ◽  
Stop Codon ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Chinese Han ◽  
Congenital Goiter ◽  
Normal Controls

Mutations in the thyroglobulin (TG) gene, which has an estimated incidence of approximately 1 in 100,000 new-borns, cause autosomal recessive congenital hypothyroidism. The mutational spectrum of the TG gene and the phenotype–genotype correlations have not yet fully been established. We report a compound heterozygous mutation in the TG gene in a Chinese twin family with congenital goiter and hypothyroidism. We also describe the gene mutation associated with the genotype–phenotype of these children with congenital goiter and hypothyroidism. The whole coding sequence of the TG gene was analyzed by direct sequence, and the identified changes in the sequence were tested for benign polymorphism by denaturing high-performance liquid chromatography screening of the mutation and sequencing 200 chromosomes from normal controls. Analysis of the TG gene of the affected twin revealed a compound heterozygous mutation, including a novel missense mutation G2687A, which is predicted to result in a glutamine to arginine substitution at codon 877, and a known nonsense mutation C7006T, predicted to result in an arginine to stop codon at codon 2317. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. This is the first report of a TG gene mutation in the Chinese Han population. Our study provides further evidence that mutations in the TG gene cause congenital goiter and hypothyroidism, demonstrates genetic heterogeneity of the mutation, and increases our understanding of phenotype–genotype correlations in congenital hypothyroidism.

A Novel Homozygous Frameshift Mutation in ITGB3 Causes Glanzmann’s Thrombasthenia

2021 ◽  
pp. 1-6
Author(s):  
XueHong Li ◽  
Jing Xu ◽  
ZhenJiang Li ◽  
Yuan Song ◽  
Yan Fei ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Chinese Family ◽  
Molecular Characteristics ◽  
Homozygous Mutation ◽  
Glanzmann’S Thrombasthenia ◽  
1000 Genomes ◽  
Whole Exome ◽  
Glanzmann's Thrombasthenia ◽  
The Family ◽  
Exon 11

The objective of this study was to elucidate the molecular characteristics of a Chinese family with Glanzmann’s thrombasthenia (GT). The proband was diagnosed with GT based on clinical manifestations, platelet aggregation, and the expression of CD41 and CD61 in platelets. Whole-exome and Sanger sequencing were used to detect genetic defects related to GT in the proband and the family of the pedigree. Whole-exome sequencing showed a c.1784–1802delinsGTCACA, p. S595Cfs*70 homozygous mutation in exon 11 of the ITGB3 gene in the proband. Heterozygous mutations were found in the proband’s parents, grandmother, uncle, aunt, and younger brother. This novel p. S595Cfs*70 ITGB3 gene mutation is not present in the 1000 Genomes and ExAC databases.

scholarly journals 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

2021 ◽  
Author(s):  
Yang Guangxian ◽  
Yin Yi ◽  
Tan Zhiping ◽  
Liu Jian ◽  
Deng Xicheng ◽  
...  
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 (CHD). 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.

scholarly journals A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 411
Author(s):  
María Lachgar ◽  
Matías Morín ◽  
Manuela Villamar ◽  
Ignacio del Castillo ◽  
Miguel Ángel Moreno-Pelayo
Keyword(s):  
Hearing Loss ◽  
Stop Codon ◽  
Coiled Coil ◽  
Premature Stop Codon ◽  
Scaffolding Protein ◽  
Common Mechanism ◽  
Chinese Family ◽  
Truncating Mutation ◽  
Spanish Family ◽  
Sensory Defect

Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype–phenotype correlations of DFNA68 hearing loss.

scholarly journals Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110059
Author(s):  
Xinwen Zhang ◽  
Shaozhi Zhao ◽  
Hongwei Liu ◽  
Xiaoyan Wang ◽  
Xiaolei Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Signs And Symptoms ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

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