Identifying modifier genes for hypertrophic cardiomyopathy

Chen, Yuanjian; Xu, Fuyi; Munkhsaikhan, Undral; Boyle, Charlie; Borcky, Theresa; Zhao, Wenyuan; Purevjav, Enkhsaikhan; Towbin, Jeffrey A.; Liao, Fang Hsuean; Williams, Robert W.; Bhattacharya, Syamal K.; Lu, Lu; Sun, Yao

doi:10.1016/j.yjmcc.2020.05.006

Cited by 15 publications

(10 citation statements)

References 35 publications

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“…Previous studies have revealed its underlying roles in the cardiovascular system. A quantitative trait locus mapping study indicated that Xirp2 serves as a candidate modifier gene for cardiac hypertrophy [54]. Moreover, in some cases of dilated cardiomyopathy, Xirp2 genes contains heterozygous mutations, and these mutations may be utilisable as a genetic diagnosis target of dilated cardiomyopathy [55].…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide analysis of the mouse LIM gene family reveals its roles in regulating pathological cardiac hypertrophy

et al. 2021

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LIM‐domain proteins have been shown to be associated with heart development and diseases. Systematic studies of LIM family members at the genome‐wide level, which are crucial to further understand their functions in cardiac hypertrophy, are currently lacking. Here, 70 LIM genes were identified and characterised in mice. The expression patterns of LIM genes differ greatly during cardiac development and in the case of hypertrophy. Both Crip2 and Xirp2 are differentially expressed in cardiac hypertrophy and during heart failure. In addition, the hypertrophic state of cardiomyocytes is controlled by the relative expression levels of Crip2 and Xirp2. This study provides a foundation for further understanding of the special roles of LIM proteins in mammalian cardiac development and hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Genome‐wide analysis of the mouse LIM gene family reveals its roles in regulating pathological cardiac hypertrophy

et al. 2021

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“…Moreover, genes involved in energy metabolism and signalling also contribute to cardiomyopathies. Apart from well known genes implicated in cardiomyopathies, there is a group of other genes referred to as modifier genes that affect these disorders [41]. According to Hamilton et al [42], ‘modifier gene’ refers to a genetic variant that can change the phenotypic outcome of an independent ‘conditioning’ variant at another locus.…”

Section: Introductionmentioning

confidence: 99%

Integrative network analysis interweaves the missing links in cardiomyopathy diseasome

Sowdhamini

2021

Preprint

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Background: Cardiomyopathies are genetic disorders resulting in an abnormal heart phenotype due to intrinsic cardiac muscle malfunction, which leads to heart failure. These are chronic disorders contributing more than 36% of heart failure in the patients. Cardiomyopathies also show co-morbidity with other diseases that frequently affect the elderly. Apart from this, many drugs used for treating other unrelated diseases cause cardio-toxicity and lead to cardiomyopathies. Unravelling the cross-talk between them is essential for useful characterization, subtyping, and better treatment of the cardiomyopathies. Results: In this work, we applied a systems biology-based analysis to explore the associations between cardiomyopathies and other morbidities. For this, we built a cardiomyopathy disease-disease network based on the combine biological data relevant to cardiomyopathies. For this, we make use of publicly available genetic, non-coding, drug and PPI datasets related to cardiomyopathies and network science tools to identify new modifiers genes that may have a role in cardiomyopathies. These modifier genes are further enriched using mouse phenotype data. Lastly, we highlight key modifier genes that may be potentially associated with cardiomyopathies. Many predicted genes link cardiomyopathies to neoplasms, metabolic and neurological disorders; some of these have been explained as case studies in this analysis. Conclusions: Traditional one drug-one target-one disease outlook alone in drug discovery is inefficient. We hereby develop an integrative approach based on primary cardiomyopathy target genes to discover new targets that provide clues in drug re-purposing, possible off-targets and hidden genetic overlap between cardiomyopathies and other morbidities. We report potential modifier genes like NOTCH4, SIRT1 that may be investigated for role in cardiomyopathy and other diseases.

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“…Incomplete penetrance and variable clinical expression are common confounding phenomena. The phenotypic variability is thought to arise, at least in part, from interactions between pathogenic variants and genetic and non-genetic modifiers [3,[11][12][13]. Variants in at least 12 genes encoding sarcomere and sarcomere-associated proteins cause HCM, the two most common of which (accounting for approximately 50% of families with HCM) are β-myosin heavy chain (MYH7) and myosin-binding protein C3 (MYBPC3) [2,3,[14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy

et al. 2021

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Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritise variants impacting MYBPC3 splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing.

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Identifying modifier genes for hypertrophic cardiomyopathy

Cited by 15 publications

References 35 publications

Genome‐wide analysis of the mouse LIM gene family reveals its roles in regulating pathological cardiac hypertrophy

Genome‐wide analysis of the mouse LIM gene family reveals its roles in regulating pathological cardiac hypertrophy

Integrative network analysis interweaves the missing links in cardiomyopathy diseasome

Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy

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