Dataset Information

Identification of a novel pathogenic variant in the MYH3 gene in a five-generation family with CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A).

ABSTRACT: BACKGROUND:Distal arthrogryposis (DA) is a group of rare Mendelian conditions that demonstrate heterogeneity with respect to genetics and phenotypes. Ten types of DAs, which collectively involve six genes, have been reported. Among them, the MYH3 gene causes several types of arthrogryposis conditions and therefore has a pivotal role in the skeletal and muscle development of the fetus. For this study, we recruited a five-generation Chinese family with members presenting DA features and phenotypic variability. Further clinical study characterized it as CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A). METHODS:Genomic DNA was extracted from eight family members, including one fetus. Whole-exome sequencing (WES) was then conducted on the proband's sample, followed by Sanger sequencing as validation for each of the participants. In silico analysis was performed. Western blotting (WB) detection and pathological staining were conducted on skeletal muscle tissue of the induced fetus after prenatal diagnosis. RESULTS:A novel heterozygous pathogenic variant, namely NM_002470.3: c.3044_3047delinsTCAATTTGTT: p.E1015_D1016delinsVNLF in the MYH3 gene, was identified and shown to be cosegregated with the condition in the subject family. This variant resulted in the replacement of amino-acid residues E1015 and D1016 by a string of VNLFs. The pregnancy was selectively terminated because the fetus was genetically affected. However, the WB and pathological results did not indicate a significant change in the norm. CONCLUSIONS:Our study expanded the variant spectrum of CPSFS1A, in addition to which it provided solid evidence for the appropriateness of genetic counseling and pregnancy management for the family. The results may also provide further insight into the molecular mechanism of MYH3.

SUBMITTER: Zhang J

PROVIDER: S-EPMC7549579 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Identification of a novel pathogenic variant in the MYH3 gene in a five-generation family with CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A).

Zhang Jing J Chen Wen-Qi WQ Wang Si-Wen SW Wang Shao-Xiong SX Yu Mei M Guo Qing Q Yu Ya-Dong YD

Molecular genetics & genomic medicine 20200807 10

<h4>Background</h4>Distal arthrogryposis (DA) is a group of rare Mendelian conditions that demonstrate heterogeneity with respect to genetics and phenotypes. Ten types of DAs, which collectively involve six genes, have been reported. Among them, the MYH3 gene causes several types of arthrogryposis conditions and therefore has a pivotal role in the skeletal and muscle development of the fetus. For this study, we recruited a five-generation Chinese family with members presenting DA features and ph ...[more]

PMID: 32767732

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is a genetic condition with a prevalence of 1:500-1:3 000. Variants in genes encoding sarcomeric proteins are mainly responsible for the disease. MYH7 gene encoding a myosin heavy chain beta, together with MYPBC3 gene are the two most commonly affected genes. The clinical presentation of this disease varies widely between individuals. This study aims to report a variant of MYH7 responsible for HCM in a five-generation family with a history of cardiac problems. Methods: The diagnosis was established according to the European Society of Cardiology HCM criteria based on two-dimensional Doppler echocardiography or cardiovascular magnetic resonance. Genetic analysis was performed using next-generation-sequencing and Sanger method. Results: The medical history of the presented family began with a prenatal diagnosis of HCM in the first child of a family with previously healthy parents. Five generations of the family had a long history of sudden cardiac death and cardiac problems. A NM_000257.4:c.2342T>A (p.Leu781Gln) variant was detected in the MYH7 gene. It was heterozygous in the proband and in all affected individuals in a large family. The variant was present in 10 affected members of the family, and was absent in 7 members. The clinical course of the disease was severe in several members of the family: three family members died of sudden cardiac death, one patient required heart transplantation, three underwent septal myectomy, and three required implantable cardioverter defibrillator (ICD) implantation. Conclusion: Herein, we report a MYH7 variant responsible for HCM. Familial HCM is inherited primarily in autosomal dominant mode, which is in accordance with our study. However, the presented family showed a broad clinical spectrum of HCM. Out of 10 family members with positive genetic testing 8 had severe presentation of the disease and 2 had a mild phenotype. This suggests that the severity of the disease may depend on other factors, most likely genetic.

Project description:Human pathogens can survive and grow in hot springs. For water quality assessment, Escherichia coli or Enterococci are the main thermotolerant enteric bacteria commonly used to estimate the load of pathogenic bacteria in water. However, most of the environmental bacteria are unculturable thus culture methods may cause bias in detection of most pathogens. Illumina sequencing can provide a more comprehensive and accurate insight into environmental bacterial pathogens, which can be used to develop better risk assessment methods and promote public health awareness. In this study, high-throughput Illumina sequencing was used to identify bacterial pathogens from five hot springs; Maiwooi, Akwar, Garbanabra, Elegedi and Gelti, in Eritrea. Water samples were collected from the five hot springs. Total community DNA was extracted from samples using the phenol-chloroform method. The 16S rRNA gene variable region (V4-V7) of the extracted DNA was amplified and library construction done according to Illumina sequencing protocol. The sequence reads (length >200 bp) from Illumina sequencing libraries ranged from 22,091 sequences in the wet sediment sample from Garbanabra to 155,789 sequences in the mat sample from Elegedi. Taxonomy was assigned to each OTU using BLASTn against a curated database derived from GreenGenes, RDPII, SILVA SSU Reference 119 and NCBI. The proportion of potential pathogens from the water samples was highest in Maiwooi (17.8%), followed by Gelti (16.7%), Akwar (13.6%) and Garbanabra (10.9%). Although the numbers of DNA sequence reads from Illumina sequencing were very high for the Elegedi (104,328), corresponding proportion of potential pathogens very low (3.6%). Most of the potential pathogenic bacterial sequences identified were from Proteobacteria and Firmicutes. Legionella and Clostridium were the most common detected genera with different species. Most of the potential pathogens were detected from the water samples. However, sequences belonging to Clostridium were observed more abundantly from the mat samples. This study employed high-throughput sequencing technologies to determine the presence of pathogenic bacteria in the five hot springs in Eritrea.

Dataset Information

Identification of a novel pathogenic variant in the MYH3 gene in a five-generation family with CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A).

Publications

Identification of a novel pathogenic variant in the MYH3 gene in a five-generation family with CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A).

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