Identification of a novel PHEX mutation in a Chinese family with X-linked hypophosphatemic rickets using exome sequencing

2015 ◽  
Vol 396 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Lamei Yuan ◽  
Song Wu ◽  
Hongbo Xu ◽  
Jingjing Xiao ◽  
Zhijian Yang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Defect ◽  
Hypophosphatemic Rickets ◽  
Chinese Family ◽  
Dental Development ◽  
Serum Phosphate Level ◽  
Loss Of Function ◽  
Hearing Impairments ◽  
Chinese Han ◽  
Teeth Abnormalities

Abstract Familial hypophosphatemic rickets (HR), the most common inherited form of rickets, is a group of inherited renal phosphate wasting disorders characterized by growth retardation, rickets with bone deformities, osteomalacia, poor dental development, and hypophosphatemia. The purpose of this study was to identify the genetic defect responsible for familial HR in a four-generation Chinese Han pedigree by exome sequencing and Sanger sequencing. Clinical features include skeletal deformities, teeth abnormalities, hearing impairments and variable serum phosphate level in patients of this family. A novel deletion mutation, c.1553delT (p.F518Sfs*4), was identified in the X-linked phosphate regulating endopeptidase homolog gene (PHEX). The mutation is predicted to result in prematurely truncated and loss-of-function PHEX protein. Our data suggest that exome sequencing is a powerful tool to discover mutation(s) in HR, a disorder with genetic and clinical heterogeneity. The findings may also provide new insights into the cause and diagnosis of HR, and have implications for genetic counseling and clinical management.

scholarly journals Whole Exome Sequencing Reveals Genetic Predisposition in a Large Family with Retinitis Pigmentosa

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Juan Wu ◽  
Lijia Chen ◽  
Oi Sin Tam ◽  
Xiu-Feng Huang ◽  
Chi-Pui Pang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinitis Pigmentosa ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Direct Sequencing ◽  
Genetic Defect ◽  
Chinese Family ◽  
Next Generation ◽  
Whole Exome ◽  
Generation Sequencing

Next-generation sequencing has become more widely used to reveal genetic defect in monogenic disorders. Retinitis pigmentosa (RP), the leading cause of hereditary blindness worldwide, has been attributed to more than 67 disease-causing genes. Due to the extreme genetic heterogeneity, using general molecular screening alone is inadequate for identifying genetic predispositions in susceptible individuals. In order to identify underlying mutation rapidly, we utilized next-generation sequencing in a four-generation Chinese family with RP. Two affected patients and an unaffected sibling were subjected to whole exome sequencing. Through bioinformatics analysis and direct sequencing confirmation, we identified p.R135W transition in the rhodopsin gene. The mutation was subsequently confirmed to cosegregate with the disease in the family. In this study, our results suggest that whole exome sequencing is a robust method in diagnosing familial hereditary disease.

A Novel 4.25kb Deletion in PAX6 in A Chinese Han Family with Congenital Aniridia Combined with Cataract and Nystagmus

2021 ◽  
Author(s):  
Tianwei Qian ◽  
Chong Chen ◽  
Caihua Li ◽  
Qiaoyun Gong ◽  
Kun Liu ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Family Members ◽  
Anterior Segment ◽  
Chinese Family ◽  
The Novel ◽  
Slit Lamp ◽  
Heterozygous Deletion ◽  
Chinese Han ◽  
Normal People ◽  
Congenital Aniridia

Abstract Background: The aim of this study is to identify the genetic defect in a Chinese family with congenital aniridia combined with cataract and nystagmus.Methods: Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilatedindirect ophthalmoscopy, anterior segment photography, and anterior segment optical coherence tomography (OCT) were performed. Blood samples were collected from all family members and genomic DNA was extracted. Genome sequencing was performed in all family members and Sanger sequencing was used to verify variant breakpoints.Results: All the thirteen members in this Chinese family, including seven patients and six normal people, were recruited in this study. The ophthalmic examination of affected patients in this family was consistent with congenital aniridia combined with cataract and nystagmus. A novel heterozygous deletion (NC_000011.10:g.31802307_31806556del) containing the 5’ region of PAX6 gene was detected that segregated with the disease. Conclusion: We detected a novel deletion in PAX6 responsible for congenital aniridia in the affected individuals of this Chinese family. The novel 4.25kb deletion in PAX6 gene of our study would further broaden the genetic defects of PAX6 associated with congenital aniridia.

scholarly journals Functional analysis of a de novo mutation c.1692 del A of the PHEX gene in a Chinese family with X-linked hypophosphataemic rickets

2019 ◽  
Vol 8 (8) ◽  
pp. 405-413
Author(s):  
Jianbo Huang ◽  
Xiaogang Bao ◽  
Wenjun Xia ◽  
Lingjun Zhu ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Sanger Sequencing ◽  
De Novo ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
De Novo Mutation ◽  
Chinese Family ◽  
Loss Of Function ◽  
Hypophosphataemic Rickets ◽  
Phex Gene

Objectives X-linked hypophosphataemic rickets (XLHR) is a disease of impaired bone mineralization characterized by hypophosphataemia caused by renal phosphate wasting. The main clinical manifestations of the disorder are O-shaped legs, X-shaped legs, delayed growth, and bone pain. XLHR is the most common inheritable form of rickets, with an incidence of 1/20 000 in humans. It accounts for approximately 80% of familial cases of hypophosphataemia and serves as the prototype of defective tubular phosphate (PO43+) transport, due to extra renal defects resulting in unregulated FGF23 activity. XLHR is caused by loss-of-function mutations in the PHEX gene. The aim of this research was to identify the genetic defect responsible for familial hypophosphataemic rickets in a four-generation Chinese Han pedigree and to analyze the function of this mutation. Methods The genome DNA samples of all members in the pedigree were extracted from whole blood. We sequenced all exons of the PHEX and FGF23 genes, as well as the adjacent splice site sequence with Sanger sequencing. Next, we analyzed the de novo mutation c.1692 del A of the PHEX gene with an online digital service and investigated the mutant PHEX with SWISS-MODEL, immunofluorescence, and protein stability detection. Results Through Sanger sequencing, we found a de novo mutation, c.1692 del A, in exon 16 of the PHEX gene in this pedigree. This mutation can make the PHEX protein become unstable and decay rapidly, which results in familial XLHR. Conclusion We have found a de novo loss-of-function mutation, c.1692 del A, in exon 16 of the PHEX gene that can cause XLHR. Cite this article: J. Huang, X. Bao, W. Xia, L. Zhu, J. Zhang, J. Ma, N. Jiang, J. Yang, Q. Chen, T. Jing, J. Liu, D. Ma, G. Xu. Functional analysis of a de novo mutation c.1692 del A of the PHEX gene in a Chinese family with X-linked hypophosphataemic rickets. Bone Joint Res 2019;8:405–413. DOI: 10.1302/2046-3758.88.BJR-2018-0276.R1.

scholarly journals A novel 4.25 kb heterozygous deletion in PAX6 in a Chinese Han family with congenital aniridia combined with cataract and nystagmus

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tianwei Qian ◽  
Chong Chen ◽  
Caihua Li ◽  
Qiaoyun Gong ◽  
Kun Liu ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Family Members ◽  
Anterior Segment ◽  
Chinese Family ◽  
The Novel ◽  
Heterozygous Deletion ◽  
Chinese Han ◽  
Indirect Ophthalmoscopy ◽  
Normal People ◽  
Congenital Aniridia

Abstract Background The aim of this study is to identify the genetic defect in a Chinese family with congenital aniridia combined with cataract and nystagmus. Methods Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilated indirect ophthalmoscopy, anterior segment photography, and anterior segment optical coherence tomography (OCT) were performed. Blood samples were collected from all family members and genomic DNA was extracted. Genome sequencing was performed in all family members and Sanger sequencing was used to verify variant breakpoints. Results All the thirteen members in this Chinese family, including seven patients and six normal people, were recruited in this study. The ophthalmic examination of affected patients in this family was consistent with congenital aniridia combined with cataract and nystagmus. A novel heterozygous deletion (NC_000011.10:g.31802307_31806556del) containing the 5′ region of PAX6 gene was detected that segregated with the disease. Conclusion We detected a novel deletion in PAX6 responsible for congenital aniridia in the affected individuals of this Chinese family. The novel 4.25 kb deletion in PAX6 gene of our study would further broaden the genetic defects of PAX6 associated with congenital aniridia.

scholarly journals A Novel Mutation in the Kringle IV Domain of LPA gene leading to Familial Hyperlipoproteinemia

2019 ◽  
Author(s):  
Youran Li ◽  
Xinyue Zhang ◽  
Yizhong Wang ◽  
Fan Gong ◽  
Xiaofei Yu ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
Chinese Family ◽  
Heterozygous Deletion ◽  
Chinese Han ◽  
Combined Use ◽  
The Family ◽  
Number Variation ◽  
Generation Sequencing

Abstract Background This study aims to investigate the clinical characterization and causative genetic defect of a four-generation Chinese Han family with hyperlipoproteinemia. Methods The combined use of next-generation sequencing and qPCR technique was performed to investigate genetic pathology of familial hyperlipoproteinemia. Results The clinical manifestations of the family members include hyperlipoproteinemia, early-onset hypertension, coronary heart disease, lipoma, cerebral infarction and even sudden death, and a novel heterozygous deletion of 3-16 exon of LPA gene was identified to be causative for the symptoms in the family. Conclusions A novel deletion in the LPA gene was identified in a Chinese family associated with hyperlipoproteinemia, which expands the spectrum of the LPA mutation and its associated phenotype. Keywords Copy number variation; Hyperlipoproteinemia; Kringle IV; Lipoprotein(a); LPA;

scholarly journals A Novel Mutation in the Kringle IV Domain of LPA Gene Leading to Familial Cardiovascular Diseases

2020 ◽  
Author(s):  
Youran Li ◽  
Xinyue Zhang ◽  
Yizhong Wang ◽  
Fan Gong ◽  
Xiaofei Yu ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Novel Mutation ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
Chinese Family ◽  
Chinese Han ◽  
Combined Use ◽  
The Family ◽  
Number Variation ◽  
Artery Disease

Abstract Background This study aims to investigate the clinical characterization and causative genetic defect of a four-generation Chinese Han family with cardiovascular diseases. Methods The combined use of next-generation sequencing and qPCR technique was performed to investigate genetic pathology of familial cardiovascular diseases. Results The clinical manifestations of the family members include coronaty artery disease, early-onset hypertension, lipoma, cerebral infarction and even unexplained sudden death, and a novel heterozygous deletion of 3-16 exon of LPA gene was identified to be causative for the symptoms in the family. Conclusions A novel deletion in the LPA gene was identified in a Chinese family associated with elevated Lp(a) levels and cardiovascular diseases, which expands the spectrum of the LPA mutation and its associated phenotypes. Keywords Copy number variation; Cardiovascular diseases；Kringle IV; Lipoprotein(a); LPA;

A novel missense mutation of CRYBA1 in a northern Chinese family with inherited coronary cataract with blue punctate opacities

2021 ◽  
pp. 112067212110083
Author(s):  
Shu-Hua Ni ◽  
Juan-Mei Zhang ◽  
Jun Zhao
Keyword(s):  
Missense Mutation ◽  
High Throughput Sequencing ◽  
Bioinformatics Analysis ◽  
Genetic Defect ◽  
Kinase Domain ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Scale Invariant ◽  
The Family ◽  
Northern Chinese

Purpose: To demonstrate the underlying genetic defect that contribute to inherited cataract in a northern Chinese pedigree. Methods: The study recruited a family pedigree with a diagnosis of bilateral coronary cataract with blue punctate opacities. Fourteen family members and 100 healthy volunteers were enrolled. DNA sample of the proband in this family were analyzed by high-throughput sequencing, which was then demonstrated by Sanger sequencing in the remained people in the family and 100 controls. The functional effect of mutant genes was investigated via bioinformatics analysis, including Polymorphism Phenotyping version2 (PolyPhen-2), Protein Variation Effect Analyzer (PROVEAN v1.1.3) Scale-Invariant Feature Transform (SIFT), and Mutation Taster. Results: In this three-generation family, a novel heterozygous mutation was found in the kinase domain of CRYBA1 gene (c.340C > T, p.R114C), which was only detected in patients in the family with inherited cataract and were not detected in the remained people in the family nor in normal people. The pathogenic effect of the mutation was verified via bioinformatics analysis. Conclusion: Our study presented the molecular experiments to confirm that a novel missense mutation of c.340 C > T located in exon 4 of CRYBA1 gene results in a bilateral coronary cataract with blue punctate opacities, which enriches the mutation spectrum of CRYBA1 gene in inherited cataract and deepens the understanding of the pathogenesis of inherited cataract.

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