A family with Milroy disease caused by the FLT4/VEGFR3 gene variant c.2774 T > A

Abstract Background Milroy disease (MD) is a rare, autosomal-dominant disorder. Variants in the Fms-related tyrosine kinase 4 (FLT4/VEGFR3) gene cause the symptoms of this disease. In this report, we investigated the variant in a large Chinese family with MD. Methods We conducted Sanger sequencing of exons 17–26 of FLT4/VEGFR3 (NM_182925.4). We assessed its pathogenicity based on the ACMG criteria and predicted it with an in silico program. Results A heterozygous substitution (NM_182925.4 (FLT4/VEGFR3):c.2774 T>A, p. (Val925Glu)) was detected in all patients with MD but not in any healthy controls. The variant was evaluated as pathogenic according to the ACMG criteria and was predicted to be pathogenic using an in silico program. Conclusions In this report, we described a large family with MD caused by a missense variant in FLT4/VEGFR3 (NM_182925.4 (FLT4/VEGFR3_v001):c.2774 T>A, p. (Val925Glu)). There are phenotypic heterogeneities among family members, and further research should be conducted to explore the possible reasons.

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A Milroy Disease Family Caused by FLT4 Gene Mutation of c.2774 T>A

10.21203/rs.3.rs-129626/v1 ◽

2021 ◽

Author(s):

Yu Sui ◽

Yongping lu ◽

Meina Lin ◽

Xiang Ni ◽

Xinren Chen ◽

...

Keyword(s):

Sanger Sequencing ◽

Autosomal Dominant ◽

Large Family ◽

Chinese Family ◽

Autosomal Dominant Disorder ◽

Amplification System ◽

Reverse Primer ◽

Dna Template ◽

Disease Family ◽

Forward Primer

Abstract Background: Milroy disease (MD) is a rare, autosomal dominant disorder. Mutations in the Fms-related tyrosine kinase 4 (FLT4) gene cause the symptoms of this disease. In this report, we investigated the mutations in a large Chinese family with MD.Methods: We conducted Sanger sequencing of exons 17–26 of the FLT4 (NM_182925.4) gene. The primers were as follows: forward, 5' CTTCATCAGCGTCGAGTGG 3' and reverse, 5' ATTATGGGCGGGTTCCTT 3'. The amplification system is as follows: 2×Biotech Power PCR Mix, 10 µl; forward primer, 0.8 µl (10 µM); reverse primer, 0.8 µl (10 µM); DNA template, 1 µl (50 ng/µl); and ddH2O, 13.4 µl. The mutation was evaluated with MutationTaster, SIFT and PolyPhen.Results: A heterozygous substitution was detected in all patients but not in any healthy controls (FLT4 gene: c.2774 T>A, p.V925E). The mutation was predicted to be pathogenic.Conclusions: In this report, we described a large family with MD caused by a missense mutation of the FLT4 gene (c.2774 T>A, p.V925E).

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Pediatric Liddle Syndrome Caused by a Novel SCNN1G Variant in a Chinese Family and Characterized by Early-Onset Hypertension

American Journal of Hypertension ◽

10.1093/ajh/hpaa037 ◽

2020 ◽

Vol 33 (7) ◽

pp. 670-675

Author(s):

Peng Fan ◽

Xiao-Cheng Pan ◽

Di Zhang ◽

Kun-Qi Yang ◽

Ying Zhang ◽

...

Keyword(s):

Early Onset ◽

In Silico ◽

Genetic Diagnosis ◽

In Silico Analysis ◽

Missense Variant ◽

Chinese Family ◽

Clinical Genetic ◽

Autosomal Dominant Disorder ◽

Liddle Syndrome ◽

Silico Analysis

Abstract BACKGROUND Liddle syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of epithelial sodium channel (ENaC)-gene-positive LS cases to conclude the clinical genetic features of LS in childhood. METHODS Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years. RESULTS Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors. CONCLUSIONS This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of γ-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents are important to prevent the development of hypertensive end-organ disease.

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A novel variant of IHH in a Chinese family with brachydactyly type 1

10.21203/rs.2.11651/v2 ◽

2019 ◽

Author(s):

Qi Yang ◽

Jin Wang ◽

Xiaoxian Tian ◽

Fei Chen ◽

Jing Lan ◽

...

Keyword(s):

Autosomal Dominant ◽

Missense Variant ◽

Chinese Family ◽

Indian Hedgehog ◽

Autosomal Dominant Disorder ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variant ◽

Active Fragment

Abstract Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog ( IHH ). The disorder is mainly characterized by shortening or missing of the middle phalanges. The following study revealed a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene after performing whole-exome sequencing in the proband of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the variants on IHH gene which contribute to the cause of BDA-1.

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A novel variant of IHH in a Chinese family with brachydactyly type 1

10.21203/rs.2.11651/v3 ◽

2020 ◽

Author(s):

Qi Yang ◽

Jin Wang ◽

Xiaoxian Tian ◽

Fei Chen ◽

Jing Lan ◽

...

Keyword(s):

Autosomal Dominant ◽

Missense Variant ◽

Chinese Family ◽

Indian Hedgehog ◽

Autosomal Dominant Disorder ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variant ◽

Active Fragment

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A novel pathogenic variant of IHH for Brachydactyly type A1

10.21203/rs.2.11651/v1 ◽

2019 ◽

Author(s):

Qi Yang ◽

Jin Wang ◽

Xiaoxian Tian ◽

Fei Chen ◽

Jing Lan ◽

...

Keyword(s):

Exome Sequencing ◽

Autosomal Dominant ◽

Missense Variant ◽

Specific Region ◽

Chinese Family ◽

Indian Hedgehog ◽

Autosomal Dominant Disorder ◽

Pathogenic Variants ◽

Whole Exome ◽

Active Fragment

Abstract Brachydactyly type A1 (BDA-1, MIM 112500) is a genetically heterogeneous autosomal-dominant disorder mainly characterized by shortening or missing of the middle phalanges. Brachydactyly type A1 (BDA-1) is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). In this study, we reported a Chinese family with 8 members affected with Brachydactyly type A1. After performing whole-exome sequencing in the proband, we identified a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the Brachydactyly type A1-related mutational spectrum of IHH gene.

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A combined in silico, in vitro and clinical approach to characterise novel pathogenic missense variants in PRPF31 in retinitis pigmentosa

10.1101/480343 ◽

2018 ◽

Author(s):

Gabrielle Wheway ◽

Liliya Nazlamova ◽

Nervine Meshad ◽

Samantha Hunt ◽

Nicola Jackson ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

In Silico ◽

Autosomal Dominant ◽

Missense Variant ◽

Incomplete Penetrance ◽

Clinical Approach ◽

Loss Of Function ◽

Autosomal Dominant Retinitis Pigmentosa ◽

Missense Variants

AbstractAt least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localise to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood.In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T>A, p.Ile114Asn.This work demonstrates how in silico modelling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

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A novel CRYBB2 mutation causes autosomal dominant cataract: A report from a Chinese family

European Journal of Ophthalmology ◽

10.1177/1120672120926450 ◽

2020 ◽

pp. 112067212092645

Author(s):

Li Juan Xu ◽

Zhi Gang Lv ◽

Ying Liu ◽

Xiang Xiang Zhang ◽

Yu Xin Cui ◽

...

Keyword(s):

Axial Length ◽

Healthy Subjects ◽

Sanger Sequencing ◽

Autosomal Dominant ◽

Pathogenic Mutation ◽

Chinese Family ◽

Rare Mutation ◽

Pathogenic Variants ◽

Lens Opacities ◽

Generation Sequencing

Purpose This study aimed to examine pathogenic mutation within one Chinese family of five-generations suffering from autosomal dominant cataract. Methods Next-generation sequencing and Sanger sequencing were used to find the pathogenic variants. Results A rare mutation, c.563G > A, in CRYBB2 gene was found in the proband that showed symptom of non-syndromic congenital autosomal dominant cataract. This mutation had been found in all affected individuals and in one healthy infant, but it did not exist between two individuals who did not develop such disease in that family, as well as in 100 healthy subjects who showed no relation with that family. Cataracts in this family varied with different severity of lens opacities and elongation of axial length. Conclusion One missense mutation c.563G > A is reported in the CRYBB2 gene among one Chinese family suffering from early-onset cataract, and associated novel phenotypes are the elongation of axial length and the types of cataract. Our results expand the spectrum of associated phenotypes of CRYBB2 mutation.

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A Novel Mutation ofSMAD3Identified in a Chinese Family with Aneurysms-Osteoarthritis Syndrome

BioMed Research International ◽

10.1155/2015/968135 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6

Author(s):

Wenwen Zhang ◽

Min Zhou ◽

Cheng Liu ◽

Chen Liu ◽

Tong Qiao ◽

...

Keyword(s):

Signal Transduction ◽

Early Onset ◽

Autosomal Dominant ◽

Novel Mutation ◽

Mutation Spectrum ◽

Chinese Family ◽

Phenotype Correlation ◽

Autosomal Dominant Disorder ◽

Arterial Tree ◽

Craniofacial Features

Aneurysms-osteoarthritis syndrome (AOS) is a recently delineated autosomal dominant disorder characterized by aneurysms, dissections, and tortuosity throughout the arterial tree in association with early onset osteoarthritis, mild craniofacial features, and skeletal and cutaneous anomalies. Previous studies have demonstrated that mutations inSMAD3, a key regulator of TGF-βsignal transduction, contribute to AOS. Here, we investigated a family of three generations affected by AOS. A novelSMAD3mutation, c.266G>A (p.C89Y), was identified and cosegregated with the affected individuals in this family. Our finding expands the mutation spectrum ofSMAD3gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype andSMAD3mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS.

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In silico analysis of CDC73 gene revealing 11 novel SNPs associated with Jaw Tumor Syndrome

10.1101/729764 ◽

2019 ◽

Author(s):

Abdelrahman H. Abdelmoneim ◽

Alaa I. Mohammed ◽

Esraa O. Gadim ◽

Mayada A.Mohammed ◽

Sara H. Hamza ◽

...

Keyword(s):

In Silico ◽

Autosomal Dominant ◽

In Silico Analysis ◽

Autosomal Dominant Disorder ◽

Variable Expression ◽

Back Ground ◽

And Function ◽

Molecular Aberrations ◽

The Impact ◽

Silico Analysis

AbstractBack groundhyperparathyroidism-jaw tumor (HPT-JT) is an autosomal dominant disorder with variable expression, with an estimated prevalence of 6.7 per 1,000 population. Genetic testing for predisposing CDC73 (HRPT2) mutations has been an important clinical advance, aimed at early detection and/or treatment to prevent advanced disease. The aim of this study is to assess the effect of SNPs on CDC73 structure and function using different bioinformatics tools.MethodComputational analysis using eight different in-silico tools including SIFT, PROVEAN, PolyPhen-2, SNAP2, PhD-SNP, SNPs&GO, PMut and Imutant were used to identify the impact on the structure and/or function of CDC73 gene that might be causing jaw tumour.ResultsFrom (733) SNPs identified in the CDC73 gene we found that only Eleven were deleterious to the function and structure of protein and expected to cause syndrome.ConclusionEleven substantial genetic/molecular aberrations in CDC73 gene were identified that could serve as actionable targets for chemotherapeutic intervention in patients whose disease is no longer surgically curable.

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

BioMed Research International ◽

10.1155/2021/6624744 ◽

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.

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