A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

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RHOMutations (p.W126L and p.A346P) in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa

Journal of Ophthalmology ◽

10.1155/2014/210947 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Satoshi Katagiri ◽

Takaaki Hayashi ◽

Masakazu Akahori ◽

Takeshi Itabashi ◽

Jo Nishino ◽

...

Keyword(s):

Molecular Modeling ◽

Retinitis Pigmentosa ◽

Autosomal Dominant ◽

Conformational Transition ◽

Novel Mutation ◽

The Novel ◽

Autosomal Dominant Retinitis Pigmentosa ◽

Modeling Analysis ◽

Whole Exome ◽

The Impact

Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO) mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP).Methods. Whole-exome sequence analysis was performed in ten adRP families. IdentifiedRHOmutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of theRHOmutation on the rhodopsin conformation was examined by molecular modeling analysis.Results. In two adRP families, we identified twoRHOmutations (c.377G>T (p.W126L) and c.1036G>C (p.A346P)), one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L) might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP.Conclusions. Our findings demonstrated that the novel mutation (p.W126L) may be associated with the phenotype of sector RP. Identification ofRHOmutations is a very useful tool for predicting disease severity and providing precise genetic counseling.

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

10.21203/rs.3.rs-21412/v3 ◽

2020 ◽

Author(s):

Xin Jin ◽

Wei Liu ◽

HouBin Huang ◽

Linghui Qv ◽

Wenqin Xv

Keyword(s):

Autosomal Dominant ◽

Novel Mutation ◽

Causative Mutation ◽

Chinese Family ◽

The Novel ◽

Slit Lamp ◽

Targeted Next Generation Sequencing ◽

Novel Variant ◽

Foveal Hypoplasia ◽

Generation Sequencing

Abstract Background: Aniridia is a kind of congenital human pan-ocular anomaly, which is related to PAX6 commonly.Methods: The ophthalmic examinations including visual acuity, slit lamp and fundoscopy examination were performed in a Chinese aniridia pedigree. 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. Phenotype related to the novel mutation included nystagmus, keratopathy, absence of iris, cataract and foveal hypoplasia.Conclusion: The novel nonsense variation in PAX6 was the cause of aniridia in this family, which expanded the spectrum of the PAX6 mutation.

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

BMC Ophthalmology ◽

10.1186/s12886-021-01848-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

X Jin ◽

W Liu ◽

LH Qv ◽

WQ X ◽

HB Huang

Keyword(s):

Autosomal Dominant ◽

Novel Mutation ◽

Causative Mutation ◽

Chinese Family ◽

The Novel ◽

Slit Lamp ◽

Targeted Next Generation Sequencing ◽

Novel Variant ◽

Foveal Hypoplasia ◽

Generation Sequencing

Abstract Background Aniridia is a kind of congenital human pan-ocular anomaly, which is related to PAX6 commonly. Methods The ophthalmic examinations including visual acuity, slit lamp and fundoscopy examination were performed in a Chinese aniridia pedigree. 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. Phenotype related to the novel mutation included nystagmus, keratopathy, absence of iris, cataract and foveal hypoplasia. Conclusions The novel nonsense variation in PAX6 was the cause of aniridia in this family, which expanded the spectrum of the PAX6 mutation.

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

10.21203/rs.3.rs-21412/v1 ◽

2020 ◽

Author(s):

Xin Jin ◽

Wei Liu ◽

HouBin Huang

Keyword(s):

Autosomal Dominant ◽

Novel Mutation ◽

Causative Mutation ◽

Chinese Family ◽

The Novel ◽

Slit Lamp ◽

Targeted Next Generation Sequencing ◽

Iris Defect ◽

Novel Variant ◽

Generation Sequencing

Abstract Background: Aniridia is a kind of congenital human panocular anomaly, which is related to PAX6 commonly.Methods: The ophthalmic examinations including visual acuity, slit lamp and fundoscopy examination were preformed in a Chinese aniridia pedigree. 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 variation in PAX6 was the cause of aniridia in this family, which expands the spectrum of the PAX6 mutation and its associated phenotype.

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A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

Translational Stroke Research ◽

10.1007/s12975-021-00926-0 ◽

2021 ◽

Author(s):

Qing Li ◽

Chengfeng Wang ◽

Wei Li ◽

Zaiqiang Zhang ◽

Shanshan Wang ◽

...

Keyword(s):

Basement Membrane ◽

Skin Biopsy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Chinese Family ◽

Heterozygous Mutation ◽

Collagen Type Iv ◽

Lacunar Infarcts ◽

Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

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

Bioscience Reports ◽

10.1042/bsr20193443 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 1

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.

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A novel mutation in the PRPH2 gene in a Chinese pedigree with retinitis pigmentosa and angle-closure glaucoma

BMC Ophthalmology ◽

10.1186/s12886-021-02064-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wei-ning Li ◽

Xiu-juan Du ◽

Yu-ting Zhang ◽

Le-yi Wang ◽

Jing Zhu

Keyword(s):

Visual Field ◽

Retinitis Pigmentosa ◽

Novel Mutation ◽

Genetic Mutation ◽

Angle Closure Glaucoma ◽

Angle Closure ◽

The Novel ◽

Progressive Loss ◽

Whole Exome ◽

Transversion Mutation

Abstract Background Retinitis pigmentosa (RP) is a rare, progressive, and hereditary disorder that leads to the progressive loss of vision and visual field, and in some cases blindness. The specific relationship between RP and glaucoma has been debated for decades. Methods In this study, we examined a Han RP family with concomitant angle-closure glaucoma (ACG), performed an inductive analysis of their clinical features and assistant results, and applied whole-exome sequencing (WES) technology for a molecular diagnosis. Results A novel transversion mutation (c.626 T > A) was identified in the peripherin-2 (PRPH2) gene in the proband, resulting in the substitution of Valine to aspartic acid in codon 209. A full ophthalmic examination showed that the proband with the c.626 T > A mutation had a typical RP manifestation, with close angles; however, the proband’s elder brother, who lacked the novel mutation, had a normal fundus and open angles. Conclusion Our results extend the genetic mutation spectrum of PRPH2 in RP, and provide evidence to support a genetic correlation between RP and ACG.

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Prenatal Diagnosis of Holt–Oram Syndrome With a Novel Mutation of TBX5 Gene: A Case Report

Frontiers in Pediatrics ◽

10.3389/fped.2021.737633 ◽

2021 ◽

Vol 9 ◽

Author(s):

Guan-nan He ◽

Xue-yan Wang ◽

Min Kang ◽

Xi-min Chen ◽

Na Xi ◽

...

Keyword(s):

Septal Defect ◽

Autosomal Dominant ◽

Novel Mutation ◽

Splice Donor ◽

Autosomal Dominant Disorder ◽

Cubitus Valgus ◽

Case Presentation ◽

Whole Exome ◽

The Right ◽

Tbx5 Gene

Background: Holt–Oram syndrome (HOS) is an autosomal dominant disorder caused by mutations of TBX5 gene.Case presentation: We report a fetus with HOS diagnosed sonographically at 23 weeks of gestation. The fetal parents are non-consanguineous. The fetus exhibited short radius and ulna, inability to supinate the hands, absence of the right thumb, and heart ventricular septal defect (VSD), while the fetal father exhibited VSD and short radius and ulna only. Fetal brother had cubitus valgus and thumb adduction, except for VSD, short radius and ulna. The pregnancy was terminated. Whole-exome sequencing (WES) revealed a novel mutation in the TBX5 (c.510+1G>A) in the fetus inherited from the father. The variant (c.510+1G>A) occurs at splice donor and may alter TBX5 gene function by impact on splicing. It was not previously reported in China.Conclusion: Our case reported a novel mutation in TBX5, which expanded the known genetic variants associated with HOS.

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

10.21203/rs.3.rs-21412/v2 ◽

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.

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Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302008000800011 ◽

2008 ◽

Vol 52 (8) ◽

pp. 1272-1276 ◽

Cited By ~ 4

Author(s):

Maria Edna de Melo ◽

Suemi Marui ◽

Vinícius Nahime de Brito ◽

Marcio Corrêa Mancini ◽

Berenice B. Mendonca ◽

...

Keyword(s):

Diabetes Insipidus ◽

Arginine Vasopressin ◽

Autosomal Dominant ◽

Novel Mutation ◽

Direct Sequencing ◽

Sequencing Analysis ◽

The Novel ◽

Autosomal Dominant Disorder ◽

Vasopressin Gene ◽

Avp Gene

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

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