Molecular Diagnosis of Hypertrophic Cardiomyopathy (HCM): In the Heart of Cardiac Disease

Melas, Marilena; Beltsios, Eleftherios T.; Adamou, Antonis; Κουμαρέλας, Κωνσταντίνος; McBride, Kim L.

doi:10.3390/jcm12010225

Cited by 17 publications

(10 citation statements)

References 69 publications

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“…We found that TINNI3 (cardiac troponin I) and CRP were associated with AF independently of NPPB. Both proteins have been previously associated with AF, either directly 53 or indirectly through conditions such as cardiomyopathy 54 , 55 and coronary heart disease. 56 , 57 The independent association of CRP may give support for atrial inflammatory signalling, an emerging model of AF pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study)

Jonmundsson,

Steindorsdottir,

Austin

et al. 2023

Europace

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Background and Aims Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4,137 serum proteins and incident AF in the prospective population-based AGES/Reykjavik study. Methods The study included 4,765 participants, of whom 1,172 developed AF. Cox proportional hazards regression models were fitted for 4,137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent AUC-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. Results The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both NT-proBNP-dependent (e.g., CHST15, ATP1B1, SVEP1) and independent components (e.g., ASPN, AKR1B, LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. NT-proBNP improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all timepoints. Conclusion The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. NT-proBNP is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.

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Section: Discussionmentioning

confidence: 99%

A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study)

Jonmundsson,

Steindorsdottir,

Austin

et al. 2023

Europace

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“…37 Although heterozygous mutations in the five key sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, and MYL2) are thought to cause more than half of known cases, acknowledging the role of nonsarcomeric genes can have important implications for diagnosis and treatment. 38,39 In Gyftopoulos et al, a GWAS was conducted to further elucidate the role of nonsarcomeric genes and discovered an association between HCM and novel variants in KMT2C and PARD3B. 40 However, as pertained to most GWAS studies, the underdiagnosis in International Classification of Diseases (ICD)-10 diagnoses confounds the representativeness of samples and should be considered in interpreting novel variants.…”

Section: Mutations In Hypertrophic Cardiomyopathymentioning

confidence: 99%

Exploring Health Care Disparities in Genetic Testing and Research for Hereditary Cardiomyopathy: Current State and Future Perspectives

Huang,

Verma,

Mok

et al. 2024

Glob Med Genet

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Background Hereditary cardiomyopathies are commonly occurring myocardial conditions affecting heart structure and function with a genetic or familial association, but the etiology is often unknown. Cardiomyopathies are linked to significant mortality, requiring robust risk stratification with genetic testing and early diagnosis. Hypothesis We hypothesized that health care disparities exist in genetic testing for hereditary cardiomyopathies within clinical practice and research studies. Methods In a narrative fashion, we conducted a literature search with online databases such as PubMed/MEDLINE, Google Scholar, EMBASE, and Science Direct on papers related to hereditary cardiomyopathies. A comprehensive analysis of findings from articles in English on disparities in diagnostics and treatment was grouped into four categories. Results Racial and ethnic disparities in research study enrollment and health care delivery favor White populations and higher socioeconomic status, resulting in differences in the development and implementation of effective genetic screening. Such disparities have shown to be detrimental, as minorities often suffer from disease progression to heart failure and sudden cardiac death. Barriers related to clinical genetic testing included insurance-related issues and health illiteracy. The underrepresentation of minority populations extends to research methodologies, as testing in ethnic minorities resulted in a significantly lower detection rate and diagnostic yield, as well as a higher likelihood of misclassification of variants. Conclusions Prioritizing minority-based participatory research programs and screening protocols can address systemic disparities. Diversifying research studies can improve risk stratification strategies and impact clinical practice.

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“…HCM has classically been recognized as a disease of the sarcomere (Figure 1C) [25]. Indeed, the most frequent genetic causes of HCM are mutations in genes encoding thick filament proteins, namely, myosin heavy chain-7 (MYH7) encoding for cardiac beta-myosin heavy chain (β-MHC), cardiac myosin binding protein C (MYBPC3), Myosin Light Chains 2 and 3 (MYL2 and MYL3), and myosin heavy chain 6 (MYH6) encoding cardiac alphamyosin heavy chain (α-MHC), with the first two accounting for more than 70% of Sarc+ cases [26].…”

Section: Genetics Of Sarc+ and Sarc− Hcmmentioning

confidence: 99%

“…In some cases, the disease may be caused by the occurrence of more than one genetic variant: the presence of double heterozygous, compound heterozygous, and homozygous mutations is often associated with more severe disease [25]. After the introduction of next-generation sequencing (NGS), an increased number of genetic variants were detected in both sarcomere and non-sarcomere genes, allowing for the early identification of genetically affected family members and preventing the unnecessary follow-up of non-carriers.…”

Section: Genetics Of Sarc+ and Sarc− Hcmmentioning

confidence: 99%

Sarcomeric versus Non-Sarcomeric HCM

Borrelli,

Losi,

Canciello

et al. 2023

Cardiogenetics

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Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disorder and is characterized by left ventricular hypertrophy (LVH), which is unexplained by abnormal loading conditions. HCM is inherited as an autosomal dominant trait and, in about 40% of patients, the causal mutation is identified in genes encoding sarcomere proteins. According to the results of genetic screening, HCM patients are currently categorized in two main sub-populations: sarcomeric-positive (Sarc+) patients, in whom the causal mutation is identified in a sarcomeric gene; and sarcomeric-negative (Sarc−) patients, in whom a causal mutation has not been identified. In rare cases, Sarc− HCM cases may be caused by pathogenic variants in non-sarcomeric genes. The aim of this review is to describe the differences in the phenotypic expression and clinical outcomes of Sarc+ and Sarc− HCM and to briefly discuss the current knowledge about HCM caused by rare non-sarcomeric mutations.

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Molecular Diagnosis of Hypertrophic Cardiomyopathy (HCM): In the Heart of Cardiac Disease

Cited by 17 publications

References 69 publications

A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study)

A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study)

Exploring Health Care Disparities in Genetic Testing and Research for Hereditary Cardiomyopathy: Current State and Future Perspectives

Sarcomeric versus Non-Sarcomeric HCM

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