A Novel Titin Truncation Variant Linked to Familial Dilated Cardiomyopathy Found in a Japanese Family and Its Functional Analysis in Genome-Edited Model Cells

Hirayama‐Yamada, Kayoko; Inagaki, Natsuko; Hayashi, Takeharu; Kimura, Akinori

doi:10.1536/ihj.20-664

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…In our research, we found that MYH11 has mutations in 7 patients, and we found two pathogenic or possibly pathogenic mutations (rs375159635, rs751495086), which may be related to the pathogenesis of Hypopharyngeal carcinoma. In addition, SDHA is mainly related to gangliomas [28-30], RYR1 is mainly related to myopathy [31,32], and TTN is mainly related to dilated cardiomyopathy [33,34]. Interestingly, we found that these three genes have mutations in more than ve patients, and all of them have two or more pathogenic or possibly pathogenic mutation sites, which indicates their potential in the pathogenesis of Hypopharyngeal carcinoma.…”

Section: Discussionmentioning

confidence: 81%

Application Value of Whole Exome Sequencing in Screening and Identifying Pathogenic Genes of Hypopharyngeal Carcinoma

Yao

Ding

Liu

et al. 2021

Preprint

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Background: Whole-exome sequencing has been used in many cancer research, but it is rarely used in Hypopharyngeal carcinoma. In our research, we performed whole-exome sequencing of DNA from 10 tumor tissue specimens from patients with hypopharyngeal cancer rather than targeted sequencing of specific genes.Methods: Whole-exome sequencing in 10 patients with hypopharyngeal carcinoma was performed to identify single nucleotide variations (SNVs) and insertions and deletions (INDELs). American College of Medical Genetics and Genomics (ACMG) guidelines were used to evaluate the pathogenicity of the selected variants. Gene Ontology (GO) and pathway enrichment were used to analyze the function and effect of mutated genes. Protein protein interaction (PPI) was analyzed by string online software.Results: 8113 mutation sites in 5326 genes were identified after strict screening. MEGF8, ITPR1, DYSF, DNAH10, CUL7, MYH14, LRP1, ASTN1, TTN, ASH1L, MYH11, KMT2C were mutated in more than 6 patients. We identified 72 pathogenic or potentially pathogenic mutations in 53 genes according to the ACMG guidelines. GO annotation and KEGG enrichment analysis show the possible effect of these pathogenic genes on cancer. Conclusion: We identified novel mutations in patients with hypopharyngeal cancer, and provided a foundation for future research on the pathogenesis of hypopharyngeal carcinoma and targeted treatment of hypopharyngeal carcinoma.

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Section: Discussionmentioning

confidence: 81%

Application Value of Whole Exome Sequencing in Screening and Identifying Pathogenic Genes of Hypopharyngeal Carcinoma

Yao

Ding

Liu

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In our research, we found that MYH11 mutated in 7 patients, and we found two pathogenic or possibly pathogenic mutations (rs375159635, rs751495086), which may be related to the pathogenesis of hypopharyngeal cancer. In addition, SDHA is mainly related to gangliomas 30 – 32 , RYR1 is mainly related to myopathy 33 , 34 , and TTN is mainly related to dilated cardiomyopathy 35 , 36 . Interestingly, we found that these three genes have mutations in more than five patients, and all of them have two or more pathogenic or possibly pathogenic mutation sites, which indicates their potential in the pathogenesis of hypopharyngeal cancer.…”

Section: Discussionmentioning

confidence: 99%

Application value of whole exome sequencing in screening and identifying novel mutations of hypopharyngeal cancer

Jian

Ding

Liu

et al. 2023

Sci Rep

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The research on targeted therapy of hypopharyngeal cancer is very scarce. The discovery of new targeted driver genes will promote the progress of hypopharyngeal cancer therapy to a great extent. In our research, whole-exome sequencing in 10 patients with hypopharyngeal cancer was performed to identify single nucleotide variations (SNVs) and insertions and deletions (INDELs). American College of Medical Genetics and Genomics (ACMG) guidelines were used to evaluate the pathogenicity of the selected variants. 8113 mutation sites in 5326 genes were identified after strict screening. We identified 72 pathogenic mutations in 53 genes according to the ACMG guidelines. Gene Ontology (GO) annotation and KEGG enrichment analysis show the effect of these genes on cancer. Protein–protein interaction (PPI) was analyzed by string online software. The validation results of the ualcan database showed that 22 of the 53 genes may be related to the poor prognosis of patients with hypopharyngeal cancer. RBM20 has the most significant correlation with hypopharyngeal cancer, and it is likely to be the driver gene of hypopharyngeal cancer. In conclusion, we found possible therapeutic targets for hypopharyngeal cancer, especially RBM20 and KMT2C. Our study provides a basis for the pathogenesis and targeted therapy of hypopharyngeal cancer.

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“… 17 To date, DCM‐causing variations in >250 genes have been implicated with the development of DCM, of which the vast majority code for sarcomere proteins, nuclear envelope proteins, cytoskeleton proteins, Z‐band proteins, intercalated disc proteins, ion channel proteins, gap junction channel proteins, RNA‐binding proteins, mitochondrial proteins, and transcriptional factor proteins. 1 , 2 , 3 , 4 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 Additionally, genome‐wide association studies have led to the discovery of many new common variants involved in DCM, in addition to novel rare variants involved in DCM. 33 Nevertheless, the genetic architecture of DCM is highly complex and diverse owing to pronounced genetical heterogeneity, and the genetic determinants underpinning DCM in a large proportion of cases remain to be identified.…”

mentioning

confidence: 99%

KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

Guo

Wang

Guo

et al. 2022

JAHA

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Background Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. Methods and Results By genome‐wide scan with microsatellite markers and genetic linkage analysis in a 4‐generation family inflicted with autosomal‐dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1–q13.3, a 4.77‐cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2‐point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole‐exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7 . Add, the E144X‐mutant KLF13 showed a defect in intracellular distribution. Conclusions This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.

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A Novel Titin Truncation Variant Linked to Familial Dilated Cardiomyopathy Found in a Japanese Family and Its Functional Analysis in Genome-Edited Model Cells

Cited by 7 publications

References 29 publications

Application Value of Whole Exome Sequencing in Screening and Identifying Pathogenic Genes of Hypopharyngeal Carcinoma

Application Value of Whole Exome Sequencing in Screening and Identifying Pathogenic Genes of Hypopharyngeal Carcinoma

Application value of whole exome sequencing in screening and identifying novel mutations of hypopharyngeal cancer

KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

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