Genetic, clinical, molecular, and pathogenic aspects of the South Asian–specific polymorphic MYBPC3Δ25bp variant

Mohammed, Arif; Nabavizadeh, Pooneh; Song, Taejeong; Desai, Darshini; Singh, Rohit; Bazrafshan, Sholeh; Kumar, Mohit; Wang, Yigang; Dhandapany, Perundurai S.; Becker, Richard C.; Kranias, Evangelia G.; Sadayappan, Sakthivel

doi:10.1007/s12551-020-00725-1

Cited by 13 publications

(11 citation statements)

References 220 publications

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“…Mutations of MYBPC3 gene are a major cause of human cardiomyopathy and associated HF [ 83 ]. MYBPC3 mutations present a high risk for HF [ 84 ]. Kissopoulou et al (2018) showed that homozygous missense MYBPC3 Pro873His mutation in human HCM is associated with an increased risk of HF development [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

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Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Glavaški

Velicki

2021

Life

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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with a prevalence of 1 in 500 people and varying clinical presentations. Although there is much research on HCM, underlying molecular mechanisms are poorly understood, and research on the molecular mechanisms of its specific clinical presentations is scarce. Our aim was to explore the molecular mechanisms shared by HCM and its clinical presentations through the automated extraction of molecular mechanisms. Molecular mechanisms were congregated by a query of the INDRA database, which aggregates knowledge from pathway databases and combines it with molecular mechanisms extracted from abstracts and open-access full articles by multiple machine-reading systems. The molecular mechanisms were extracted from 230,072 articles on HCM and 19 HCM clinical presentations, and their intersections were found. Shared molecular mechanisms of HCM and its clinical presentations were represented as networks; the most important elements in the intersections’ networks were found, centrality scores for each element of each network calculated, networks with reduced level of noise generated, and cooperatively working elements detected in each intersection network. The identified shared molecular mechanisms represent possible mechanisms underlying different HCM clinical presentations. Applied methodology produced results consistent with the information in the scientific literature.

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Section: Discussionmentioning

confidence: 99%

“…Incomplete penetrance [ 96 ] and haploinsufficiency [ 84 , 99 ] also complicate interpretations of genotype-phenotype associations [ 96 ] and the prediction of clinical presentations. Phenotypic effects in cases of incomplete penetrance are even more responsive to the presence of other genetic and environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Glavaški

Velicki

2021

Life

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“…Genetic analysis of this case alone would have determined that these variants were likely to cause abnormal protein function and were associated with cause of death. In particular, the KCNE1 , MYBPC3 , and AKAP9 genes that were associated with LQTS or cardiomyopathy would have been suspicious as genes associated with cause of death because of an AD mode of inheritance 27 , 37 , 38 . These were sporadic cases without any family history of sudden death, and none of the AD-inherited arrhythmia-related gene variants in these cases were de novo.…”

Section: Discussionmentioning

confidence: 99%

Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis

Shingu

Murase

Yamamoto

et al. 2021

Sci Rep

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In sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

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“…Intronic variants in MYBPC3 in the context of hypertrophic cardiomyopathy have also been identified [ 14 , 15 , 16 ] and, in the last few years, have focused on one specific intronic MYBPC3 variant c.1224-52G>A (IVS13-52G>A) [ 17 , 18 , 19 , 20 , 21 ]. Specifically, Bagnall et al reported on a cohort of unrelated gene-elusive probands with HCM that had undergone genome sequencing, in which they identified the intronic MYBPC3 variant c.1224-52G>A in two adult male family members, as well as an adult proband from another family [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Two Homozygous Variants in MYBPC3 and SMYD1 Genes Associated with Severe Infantile Cardiomyopathy

Szulik

Reyes‐Múgica

Marker

et al. 2023

Genes

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Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the MYBPC3 and SMYD1 genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous MYBPC3 variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the SMYD1 gene. The second patient, the proband’s sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous MYBPC3 variant. While this specific MYBPC3 variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel SMYD1 variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology.

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Genetic, clinical, molecular, and pathogenic aspects of the South Asian–specific polymorphic MYBPC3Δ25bp variant

Cited by 13 publications

References 220 publications

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis

Identification of Two Homozygous Variants in MYBPC3 and SMYD1 Genes Associated with Severe Infantile Cardiomyopathy

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