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

Guo, Binbin; Jin, Jie‐Yuan; Yuan, Zhongwei; Zeng, Lei; Xiang, Rong

doi:10.1155/2021/6678531

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…Berry Genomics Company Limited (Chengdu, China) performed an exome capture, a high-throughput sequencing, and a common filtering, as described in a previous article ( 9 ). In this study, we retained all synonymous variants.…”

Section: Methodsmentioning

confidence: 99%

Case Report: Identification of the First Synonymous Variant of Myosin Binding Protein C3 (c.24A>C, p.P8P) Altering RNA Splicing in a Cardiomyopathy and Sudden Cardiac Death Case

Jin

Xiao

Dong

et al. 2022

Front. Cardiovasc. Med.

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BackgroundSudden cardiac death (SCD), based on sudden cardiac ejection cessation, is an unexpected death. Primary cardiomyopathies, including dilated cardiomyopathy (DCM), are one of main causes of SCD. The DCM is characterized by a cardiac dilatation and a reduced systolic function with a prevalence of 1/250 in adults. The DCM has been reported with more than 60 disease-causing genes, and MYBPC3 variants are one of the most common and well-known causes of DCM.MethodsWe identified a 29-year-old female who died of SCD. We performed a whole-exome sequencing (WES) to detect her genetic etiology and used minigene modeling and immunohistochemistry staining to verify the pathogenicity.ResultsWe determined that the woman died of SCD caused by DCM due to an identified novel synonymous variant of MYBPC3 (NM_000256.3: c.24A>C, p.P8P) in the deceased. The variant can result in abnormal splicing, which was confirmed by minigene models and immunohistochemistry staining.ConclusionWe may have identified the first deleterious synonymous variant of MYBPC3 in an SCD case and verified its significant impact on RNA splicing. Our description enriched the spectrum of MYBPC3 variants and emphasized the significance of synonymous variants that are always disregarded in genetic screening.

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Section: Methodsmentioning

confidence: 99%

Case Report: Identification of the First Synonymous Variant of Myosin Binding Protein C3 (c.24A>C, p.P8P) Altering RNA Splicing in a Cardiomyopathy and Sudden Cardiac Death Case

Jin

Xiao

Dong

et al. 2022

Front. Cardiovasc. Med.

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“…Variants with a mean coverage ≥100 were retained. Data analysis followed the methods of Jin et al [14,15]. After filtering of common variants (frequency ≥0.01) with the 1000 Genomes Project database (https://www.genome.…”

Section: Target Sequencingmentioning

confidence: 99%

Identification of Arrhythmia-Associated Gene Mutations in Chinese Patients with Primary Electrical Disorders or Sudden Cardiac Death

Liu,

Hu,

Zhang

et al. 2024

CVIA

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Background: Sudden cardiac death (SCD), unexpected death based on sudden cardiac ejection cessation, accounts for 15–20% of unnatural deaths in developed countries. Primary electrical disorders (PEDs), a group of cardiac rhythm abnormalities without detectable structural heart disease, are a major cause of SCD in people younger than 35 years of age. Cardiac muscle contraction and relaxation are triggered by the action potential (AP), which is generated by ionic changes across the cell membrane. Thus, PEDs are influenced by mutations in AP-associated genes, such as KCNE1 and RYR2. Methods: We recruited six patients with SCD and 42 patients with arrhythmia with onset under the age of 25, and used targeted sequencing to determine the genetic etiologies. Results: We identified five mutations (RYR2: c.12269C>T, p.P4090L; KCNE1: c.169T>C, p.F57L; KCNQ1: c.853A>C, p.K285Q; KCNH2: c.793T>C, p.C265R, and TRPM4: c.2985_3012del, p.E996Gfs*118) in five families with PED/SCD. Conclusions: We detected five mutations and expanded the mutation spectrum of PED-associated genes, thus contributing to the clinical diagnosis of PED.

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“…Pseudoachondroplasia (PSACH, MIM 177170) is a rare familial inherited disease with an estimated prevalence of 1 in 60,000 (Guo et al., 2021). The outward appearances of patients include dwarf, short fingers, knee varus or valgus, and waddling gait.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of a rare pathogenic variant c.875G > A, p.(Cys292Tyr) in COMP

Yin

Zhu

Jiang

et al. 2023

Annals of Human Genetics

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BackgroundThe protein encoded by the cartilage oligomeric matrix protein (COMP) gene is a noncollagenous extracellular matrix (ECM) protein that is important for chondrocyte formation and growth. Variations in the COMP gene cause pseudoachondroplasia (PSACH), which is mainly characterized by short‐limbed dwarfing in the clinic.AimsTo characterize the function of a rare pathogenic variant in the COMP gene (c.875G > A, p.Cys292Tyr).Materials & MethodsWe performed 3D structural analysis, in vitro expression analysis, and immunofluorescence to characterize the effects of the variant on protein structure, expression, and cellular localization respectively.ResultsVariation modeling showed that the interactions between amino acids were changed after the variation, and there were 31 changes in the secondary structure of mutant COMP (MT‐COMP). Western blot showed that the intracellular quantity of MT‐COMP was higher than the wild‐type COMP (WT‐COMP). Cellular immunofluorescence results showed that WT‐COMP was less abundant and homogenously distributed in cells, while the MT‐COMP accumulated in the cytoplasm.DiscussionHerein, we report a variant of COMP in a Chinese family with PSACH. We have shown that the rare missense variant, COMP c.875G > A, previously reported in ClinVar and identified in our patient, results in excessive accumulation of mutant protein in the cytoplasm, and is therefore pathogenic.ConclusionThrough in silico and experimental analyses, we provide evidence that COMP c.875G > A is the likely cause of PSACH in a Chinese family.

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

Cited by 4 publications

References 32 publications

Case Report: Identification of the First Synonymous Variant of Myosin Binding Protein C3 (c.24A>C, p.P8P) Altering RNA Splicing in a Cardiomyopathy and Sudden Cardiac Death Case

Case Report: Identification of the First Synonymous Variant of Myosin Binding Protein C3 (c.24A>C, p.P8P) Altering RNA Splicing in a Cardiomyopathy and Sudden Cardiac Death Case

Identification of Arrhythmia-Associated Gene Mutations in Chinese Patients with Primary Electrical Disorders or Sudden Cardiac Death

Functional characterization of a rare pathogenic variant c.875G > A, p.(Cys292Tyr) in COMP

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