Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

Franaszczyk, Maria; Truszkowska, Grażyna; Chmielewski, Przemysław; Rydzanicz, Małgorzata; Kosińska, Joanna; Rywik, Tomasz; Biernacka, Anna; Śpiewak, Mateusz; Kostrzewa, Grażyna; Stępień-Wojno, Małgorzata; Stawiński, Piotr; Bilińska, Maria; Krajewski, Paweł; Zieliński, Tomasz; Lutyńska, Anna; Bilińska, Zofia T.; Płoski, Rafał

doi:10.3390/jcm9020370

Cited by 13 publications

(9 citation statements)

References 56 publications

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“…The variant (c.3197C>G; p.(Pro1066Arg)) in exon 29 of the MYBPC3 gene (NM_000256.3) was previously classified as an uncertain significance variant by two submitters in the ClinVar database (ClinVar variation ID: 1171602). This change has not been reported in gnomAD; however, it was recently reported in an individual with restrictive cardiomyopathy, who also carried a pathogenic variant in the MYH7 gene (c.2302G>A; p.(Gly768Arg)), which was also in his unaffected father [ 15 ]. The majority of in silico pathogenicity prediction tools support a deleterious effect on the gene and genomic position is conserved.…”

Section: Resultsmentioning

confidence: 87%

Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family

Rodríguez‐López¹,

Garcı́a-Planells

Martínez-Matilla

et al. 2022

Life

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MYPBC3 and MYH7 are the most frequently mutated genes in patients with hereditary HCM. Homozygous and compound heterozygous genotypes generate the most severe phenotypes. A 35-year-old woman who was a homozygous carrier of the p.(Pro1066Arg) variant in the MYBPC3 gene, developed HCM phenocopy associated with left ventricular noncompaction and various degrees of conduction disease. Her father, a double heterozygote for this variant in MYBPC3 combined with the variant p.(Gly1931Cys) in the MYH7 gene, was affected by HCM. The variant in MYBPC3 in the heterozygosis-produced phenotype was neither in the mother nor in her only sister. Familial segregation analysis showed that the homozygous genotype p.(Pro1066Arg) was located in a region of 26 Mb loss of heterozygosity due to some consanguinity in the parents. These findings describe the pathogenicity of this variant, supporting the hypothesis of cumulative variants in cardiomyopathies, as well as the modulatory effect of the phenotype by other genes such as MYH7. Advancing HPO phenotyping promoted by the Human Phenotype Ontology, the gene–disease correlation, and vice versa, is evidence for the phenotypic heterogeneity of familial heart disease. The progressive establishment of phenotypic characteristics over time also complicates the clinical description.

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Section: Resultsmentioning

confidence: 87%

Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family

Rodríguez‐López¹,

Garcı́a-Planells

Martínez-Matilla

et al. 2022

Life

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“…45 The UNC45A gene has been characterized as potential de novo mosaic variant in sporadic cardiomyopathy. 46 KLRN is a Rho Guanine Nucleotide Exchange Factor ( GEF ), which is downregulated in ICM and NICM hearts. 47 A-Kinase Anchoring Protein 13 ( AKAP13 ) promotes downstream hypertrophic gene expression, mediated at least in part via HDAC5 phosphorylation and MEF2 -mediated transcription in TAC model of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiling of the Failing Human Heart with Mechanical Unloading IdentifiesLINC00881as an Essential Regulator of Calcium Handling in the Cardiomyocyte

Liao

Kennel

Liu

et al. 2022

Preprint

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Background: Human heart failure is characterized by global alterations in the myocardial DNA methylation profile, yet little is known about epigenetic regulation of non- coding transcripts and potential reversibility of DNA methylation with left ventricular assist device (LVAD) support. Method: Genome-wide mapping of myocardial DNA methylation was performed in 36 patients with end-stage heart failure at the time of LVAD implant, 8 patients at the time of LVAD explant, and 7 non-failing controls using high-density bead array platform. Transcriptomic and functional studies were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSCs). Results: Etiology-specific analysis revealed 2079 differentially methylated positions (DMPs) in ischemic cardiomyopathy (ICM) and 261 DMPs in non-ischemic cardiomyopathy (NICM). 192 DMPs were common to ICM and NICM. Analysis of paired samples before and after LVAD support demonstrated reverse methylation of only 3.2% of HF-specific DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated (HTRA1, FAM65A, FBXO16, EFCAB13, AKAP13, RPTOR) or hypermethylated and downregulated (TBX3) in ICM and NICM patients. A novel cardiac-specific super-enhancer lncRNA (LINC00881) is hypermethylated and downregulated in the failing human heart. LINC00881 is an upstream regulator of sarcomere and calcium channel gene expression including MYH6, CACNA1C, and RYR2. LINC00881 knockdown significantly reduced peak calcium amplitude in the beating human iPSCs. Conclusions: Failing human heart exhibits etiology-specific changes in DNA methylation including coding and non-coding regions, which are minimally reversible with mechanical unloading. Epigenetic reprogramming may be necessary to achieve transcriptional normalization and sustained clinical recovery from heart failure.

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“…The incidence of de novo mutations has recently emerged to be higher than previously expected in several different diseases, with important implications for genetic counseling [ 17 , 18 , 19 , 20 , 21 , 22 ]. A de novo mutation may occur either at a pre-zygotic stage (e.g., in gametes) or in dividing post-zygotic cells [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma

Azzollini

Schiavello

Buttarelli

et al. 2020

Cancers

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Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42–77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.

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Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

Cited by 13 publications

References 56 publications

Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family

Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family

Genome-Wide DNA Methylation Profiling of the Failing Human Heart with Mechanical Unloading IdentifiesLINC00881as an Essential Regulator of Calcium Handling in the Cardiomyocyte

Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma

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