scholarly journals Identification of a Mutation in the Novel Compound Heterozygous CFTR in a Chinese Family with Cystic Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Hongxia Shao ◽  
Jingna Hua ◽  
Qi Wu ◽  
Xiaoge Li ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Manifestations ◽  
Chinese Patients ◽  
Clinical Samples ◽  
Compound Heterozygous Mutation ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
The Novel ◽  
Airway Infections ◽  
The Family

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders among Caucasians of Northern European descent but is uncommon in the Chinese population. Objectives. To elucidate the mutation in the novel compound heterozygous CFTR causing CF in Chinese family. Materials and Methods. Clinical samples were obtained from a Chinese family, the brother and sister with recurrent airway infections, hypoxemia and obstructive ventilatory impairment, sinusitis, clubbed fingers, salty sweat, and nasal polyposis. We performed whole-exome sequencing on the family and validated all potential variants by Sanger sequencing. Results. Next-generation sequencing showed a novel compound heterozygous CFTR mutation (c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162∗) which resulted in CF in the family. Conclusions. As this mutation is consistent with the observed clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that their CF phenotypes are caused by the compound heterozygous mutation, c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162∗. As c.400 A > G is not currently listed in the Cystic Fibrosis Mutation Database, this information, regarding the CF-causing mutations in two Chinese patients, is of interest.

scholarly journals Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Chunli Wei ◽  
Ting Xiao ◽  
Jingliang Cheng ◽  
Jiewen Fu ◽  
Qi Zhou ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
The Novel ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Compound Heterozygous Variants ◽  
Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

A novel variant in PAX6 as the cause of aniridia in a Chinese family

2020 ◽  
Author(s):  
Xin Jin ◽  
Wei Liu ◽  
HouBin Huang
Keyword(s):  
Nonsense Mutation ◽  
Novel Mutation ◽  
Causative Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Iris Defect ◽  
The Family ◽  
Novel Variant ◽  
Pax6 Mutation

Abstract Background: Aniridia is a kind of congenital human panocular anomaly, which is related to PAX6 commonly. Methods: A Chinese Aniridia pedigree underwent ophthalmic examinations, including visual acuity, slit lamp and fundoscopy examination. The targeted next-generation sequencing of Aniridia genes was used to identify the causative mutation. Results: A novel heterozygous PAX6 nonsense mutation c.619A>T (p.K207*) was identified in the Chinese autosomal dominant family with aniridia. Phenotypes related to the novel mutation include nystagmus, iris defect, cataract and absence of macular fovea. Conclusion: The novel nonsense mutation in PAX6 was responsible for aniridia phenotype in the family. which expands the spectrum of the PAX6 mutation and its associated phenotype.

scholarly journals Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sha Zhao ◽  
Zhenqing Luo ◽  
Zhenghui Xiao ◽  
Liping Li ◽  
Rui Zhao ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Chinese Population ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Cohen Syndrome ◽  
The Family ◽  
Sporadic Cases

Abstract Background Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. Case presentation A Chinese family with two offspring–patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. Conclusions This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.

A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

Cephalalgia ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 1382-1395
Author(s):  
Wenjing Tang ◽  
Meichen Zhang ◽  
Enchao Qiu ◽  
Shanshan Kong ◽  
Yingji Li ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Pathogenic Mutation ◽  
Familial Hemiplegic Migraine ◽  
Chinese Family ◽  
Hemiplegic Migraine ◽  
Pathogenic Potential ◽  
The Family

Background ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation. Methods Clinical manifestations in the family were recorded. Blood samples from patients and the unaffected members were collected for whole-exome sequencing to identify the pathogenic mutation. Seven online softwares (SIFT, PolyPhen-2, PROVEAN, PANTHER, MutationTaster2, MutationAssessor and PMut) were used for predicting the pathogenic potential of the mutation. PredictProtein, Jpred 4 and PyMOL were used to analyze structural changes of the protein. The mutation function was further tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Results All patients in the family had typical hemiplegic migraine attacks. Co-segregation of the mutation with the migraine phenotype in four generations, with 10 patients, was completed. The identified novel mutation, G762S in ATP1A2, exhibited the disease-causing feature by all the predictive softwares. The mutation impaired the local structure of the protein and decreased cell viability. Conclusion G762S in ATP1A2 is a novel pathogenic mutation identified in a Chinese family with familial hemiplegic migraine, which causes loss of function by changing the protein structure of the Na+/K+-ATPase α2 subunit.

scholarly journals A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings

2021 ◽  
Vol 12 ◽  
Author(s):  
Yeran Yang ◽  
Jiwei Chen ◽  
Hong Qin ◽  
Yaqiong Jin ◽  
Li Zhang ◽  
...  
Keyword(s):  
Cell Line ◽  
Brca2 Gene ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Rna Seq ◽  
The Family ◽  
Neuroblastic Tumors ◽  
Family Case ◽  
The Impact

ObjectivesTo investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.Materials and MethodsOne family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.ResultsA novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings’ mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.ConclusionIn summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.

scholarly journals Methods for Extraction and Detection of Bacteriophage DNA from the Sputum of Patients with Cystic Fibrosis

2020 ◽  
Author(s):  
Elizabeth B Burgener ◽  
Patrick R Secor ◽  
Michael C Tracy ◽  
Johanna M Sweere ◽  
Elisabeth M Bik ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Samples ◽  
Proof Of Concept ◽  
Chronic Infections ◽  
Optimized Protocol ◽  
Airway Infections ◽  
Viral Communities ◽  
Microbial Dna ◽  
The Impact ◽  
Specific Bacteriophage

AbstractThere is increasing interest in the pulmonary microbiome’s bacterial and viral communities, particularly in the context of chronic airway infections in cystic fibrosis (CF). However, the isolation of microbial DNA from the sputum from patients with CF is technically challenging and the optimal protocols for the analysis of viral species, including bacteriophage, from clinical samples remains challenging. Here, we evaluate a set of methods developed for processing and analyzing sputum from patients with CF with a particular emphasis on detecting bacteriophage viron-derived nucleic acid. We evaluate the impact of bead-beating, deoxyribonuclease digestion, and heating steps in these protocols focusing on the quantitative assessment of Pseudomonas aeruginosa and Pf bacteriophage in sputum as a proof of concept. Based on these comparative data, we describe an optimized protocol for processing sputum from patients with CF and isolating DNA for PCR or sequencing-based studies. These studies will facilitate future assessments of bacteriophage and bacteria in sputum from patients with CF.Author SummaryPatients with cystic fibrosis (CF) have thickened secretions and develop chronic infections in their airways. While we culture bacterial pathogens from expectorated sputum this method favors detection of certain organisms. There is greater understanding that the microbiome with in the airway of patients with cystic fibrosis is varied and contains more than just the bacteria that we selectively culture. Processing sputum is difficult as it is very thick. There are many different ways to process sputum depending on what aspect of the sputum is to be studied. We have an interest in a specific bacteriophage, or a virus that infects bacteria. We sought to find the best method to take sputum from a CF patient and extract DNA so that we could detect both bacteria and bacteriophage DNA. We compared different methods that included different combinations of heat, mechanical homogenization, chemical lysis and DNA extraction by commercially available kits. We describe the method we found easiest to execute and produced the best yield for detection of both bacteria and bacteriophage. Our purpose of publishing this method in detail is to facilitate further study of viral and bacterial communities in the sputum of patients with CF.

scholarly journals Vasculitis in a patient with mevalonate kinase deficiency (MKD): a case report

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ebun Omoyinmi ◽  
Dorota Rowczenio ◽  
Neil Sebire ◽  
Paul A. Brogan ◽  
Despina Eleftheriou
Keyword(s):  
Diagnostic Delay ◽  
Clinical Manifestations ◽  
Lower Limbs ◽  
Cutaneous Vasculitis ◽  
Targeted Treatment ◽  
Compound Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Cytotoxic Treatment

Abstract Background Mevalonate kinase deficiency (MKD) is a rare autoinflammatory condition caused by biallelic loss-of-function (LOF) mutations in mevalonate kinase (MVK) gene encoding the enzyme mevalonate kinase. Patients with MKD display a variety of non-specific clinical manifestations, which can lead to diagnostic delay. We report the case of a child presenting with vasculitis that was found by genetic testing to be caused by MKD, and now add this autoinflammatory disease to the ever-expanding list of causes of monogenic vasculitides. Case presentation A 2-year-old male presented with an acute 7-day history of high-grade fever, abdominal pain, diarrhoea, rectal bleeding and extensive purpuric and necrotic lesions, predominantly affecting the lower limbs. He had been suffering from recurrent episodes of fever from early in infancy, associated with maculopapular/petechial rashes triggered by intercurrent infection, and after vaccines. Extensive infection screen was negative. Skin biopsy revealed small vessel vasculitis. Visceral digital subtraction arteriography was normal. With a diagnosis of severe idiopathic cutaneous vasculitis, he was treated with corticosteroids and mycophenolate mofetil. Despite that his acute phase reactants remained elevated, fever persisted and the vasculitic lesions progressed. Next-generation sequencing revealed compound heterozygous mutation in MVK c.928G > A (p.V310M) and c.1129G > A (p.V377I) while reduced mevalonate enzyme activity was confirmed suggesting a diagnosis of MKD as a cause of the severe vasculitis. Prompt targeted treatment with IL-1 blockade was initiated preventing escalation to more toxic vasculitis therapies and reducing unnecessary exposure to cytotoxic treatment. Conclusions Our report highlights the broad clinical phenotype of MKD that includes severe cutaneous vasculitis and emphasizes the need to consider early genetic screening for young children presenting with vasculitis to exclude a monogenic vasculitis which may be amenable to targeted treatment.

scholarly journals Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Qin Xiang ◽  
Yanna Cao ◽  
Hongbo Xu ◽  
Zhijian Yang ◽  
Liang Tang ◽  
...  
Keyword(s):  
Family Members ◽  
Major Facilitator Superfamily ◽  
Chinese Family ◽  
Macular Dystrophy ◽  
Compound Heterozygous ◽  
The Novel ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Major Facilitator ◽  
Mfsd8 Gene

Purpose. To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods. Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results. Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion. The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

Two Novel Mutations Cause Hereditary Antithrombin Deficiency in a Chinese Family

2019 ◽  
Vol 143 (3) ◽  
pp. 260-265
Author(s):  
Haiyue Zhang ◽  
Siqi Liu ◽  
Shasha Luo ◽  
Yanhui Jin ◽  
Lihong Yang ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
Gene Sequencing ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
The Novel ◽  
Normal Range ◽  
Novel Mutations ◽  
Antithrombin Deficiency ◽  
At Deficiency

Objective: To study the molecular basis of hereditary antithrombin (AT) deficiency in a Chinese family. It will help us understand the pathogenesis of this type of disease. Method: AT activity (AT:A) and the AT antigen (AT:Ag) level were tested by chromogenic substrate and immunoturbidimetry, respectively. To identify the novel mutations, SERPINC1 gene sequencing was carried out. The possible impact of the mutations was analyzed by model and bioinformatic analyses. Results: AT:A and the AT:Ag level of the proband were 43% and 113 mg/L (normal range: 98–119% and 250–360 mg/L), respectively. Sequencing analysis revealed compound heterozygous mutations, including a frameshift mutation (c.318_319insT) resulting in Asn75stop and a missense mutation (c.922G>T) resulting in Gly276Cys. The bioinformatic and model analyses indicated that these mutations may disrupt the function and structure of the AT protein. Conclusion: We detected 2 novel heterozygous mutations (c.318_319insT and c.922G>T) in the proband, and these were associated with decreased AT:A.

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