BackgroundMutations in LMNA gene, encoding Lamin A/C, cause a diverse array of phenotypes, collectively referred to as laminopathies. The most common manifestation is dilated cardiomyopathy (DCM), occurring in conjunction with variable skeletal muscle involvement but without involvement of the coronary arteries. Much less commonly, LMNA mutations cause progeroid syndromes, whereby an early-onset coronary artery disease (CAD) is the hallmark of the disease. We report a hitherto unreported compound cardiac phenotype, dubbed as “non-syndromic cardiac progeria”, in a young patient who carried a rare pathogenic variant in the LMNA gene and developed progressive degeneration of various cardiac structures, as seen in the elderly. The phenotype resembled the progeroid syndromes, except that it was restricted to the heart and did not involve other organs.Case presentationThe patient was a well-developed Caucasian female who presented at age 29 years with an acute myocardial infarction (MI) and was found to have extensive CAD. She had none of the conventional risk factors for atherosclerosis. She underwent coronary artery bypass surgery but continued to require multiple percutaneous coronary interventions for symptomatic obstructive coronary lesions. During the course of next 10 years, she developed mitral regurgitation, degenerative mitral and aortic valve diseases, atrial flutter, and progressive conduction defects. She died from progressive heart failure with predominant involvement of the right ventricle and severe tricuspid regurgitation. Cardiac phenotype in this young patient resembled degenerative cardiac diseases of the elderly and the progeroid syndromes. However, in contrast to the progeroid syndromes, the phenotype was restricted to the heart and did not involve other organs. Thus, the phenotype was dubbed as a non-syndromic cardiac progeria.Genetic screening of several cardiomyopathy genes, including LMNA, which is a causal gene for progeroid syndromes, led to identification of a very rare pathogenic p.Asp300Asn variant in the LMNA gene.ConclusionsWe infer that the LMNA p.Asp300Asn mutation is pathogenic in non-syndromic cardiac progeria. Mutations involving codon 300 in the LMNA gene have been associated with progeroid syndromes involving multiple organs. Collectively, the data provide credence to the causal role of p.Asp300Asn mutation in the pathogenesis of non-syndromic cardiac progeria.

BackgroundAdvances in the nucleic acid sequencing technologies have ushered in the era of genetic-based “precision medicine”. Applications of the genetic discoveries to practice of medicine, however, are hindered by phenotypic variability of the genetic variants. The report illustrates extreme pleiotropic phenotypes associated with an established causal mutation for hereditary cardiomyopathy.Case presentationWe report a 61-year old white female who presented with syncope and echocardiographic and cardiac magnetic resonance (CMR) imaging findings consistent with the diagnosis of hypertrophic cardiomyopathy (HCM). The electrocardiogram, however, showed a QRS pattern resembling an Epsilon wave, a feature of arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole exome sequencing (mean depth of coverage of exons 178X) analysis did not identify a pathogenic variant in the known HCM genes but identified an established causal mutation for ARVC. The mutation involves a canonical splice accepter site (c.2146-1G > C) in the PKP2 gene, which encodes plakophillin 2. Sanger sequencing confirmed the mutation. PKP2 is the most common causal gene for ARVC but has not been implicated in HCM. Findings on echocardiography and CMR during the course of 4-year follow up showed septal hypertrophy and a hyperdynamic left ventricle, consistent with the diagnosis of HCM. However, neither baseline nor follow up echocardiography and CMR studies showed evidence of ARVC. The right ventricle was normal in size, thickness, and function and there was no evidence of fibro-fatty infiltration in the myocardium.ConclusionsThe patient carries an established pathogenic mutation for ARVC and a subtle finding of ARVC but exhibits the classic phenotype of HCM, a contrasting phenotype to ARVC. The case illustrates the need for detailed phenotypic characterization for patients with hereditary cardiomyopathies as well as the challenges physicians face in applying the genetic discoveries in practicing genetic-based “precision medicine”.

BackgroundMutations in LMNA gene, encoding Lamin A/C, cause a diverse array of phenotypes, collectively referred to as laminopathies. The most common manifestation is dilated cardiomyopathy (DCM), occurring in conjunction with variable skeletal muscle involvement but without involvement of the coronary arteries. Much less commonly, LMNA mutations cause progeroid syndromes, whereby an early-onset coronary artery disease (CAD) is the hallmark of the disease. We report a hitherto unreported compound cardiac phenotype, dubbed as “non-syndromic cardiac progeria”, in a young patient who carried a rare pathogenic variant in the LMNA gene and developed progressive degeneration of various cardiac structures, as seen in the elderly. The phenotype resembled the progeroid syndromes, except that it was restricted to the heart and did not involve other organs.Case presentationThe patient was a well-developed Caucasian female who presented at age 29 years with an acute myocardial infarction (MI) and was found to have extensive CAD. She had none of the conventional risk factors for atherosclerosis. She underwent coronary artery bypass surgery but continued to require multiple percutaneous coronary interventions for symptomatic obstructive coronary lesions. During the course of next 10 years, she developed mitral regurgitation, degenerative mitral and aortic valve diseases, atrial flutter, and progressive conduction defects. She died from progressive heart failure with predominant involvement of the right ventricle and severe tricuspid regurgitation. Cardiac phenotype in this young patient resembled degenerative cardiac diseases of the elderly and the progeroid syndromes. However, in contrast to the progeroid syndromes, the phenotype was restricted to the heart and did not involve other organs. Thus, the phenotype was dubbed as a non-syndromic cardiac progeria.Genetic screening of several cardiomyopathy genes, including LMNA, which is a causal gene for progeroid syndromes, led to identification of a very rare pathogenic p.Asp300Asn variant in the LMNA gene.ConclusionsWe infer that the LMNA p.Asp300Asn mutation is pathogenic in non-syndromic cardiac progeria. Mutations involving codon 300 in the LMNA gene have been associated with progeroid syndromes involving multiple organs. Collectively, the data provide credence to the causal role of p.Asp300Asn mutation in the pathogenesis of non-syndromic cardiac progeria.

BackgroundAdvances in the nucleic acid sequencing technologies have ushered in the era of genetic-based “precision medicine”. Applications of the genetic discoveries to practice of medicine, however, are hindered by phenotypic variability of the genetic variants. The report illustrates extreme pleiotropic phenotypes associated with an established causal mutation for hereditary cardiomyopathy.Case presentationWe report a 61-year old white female who presented with syncope and echocardiographic and cardiac magnetic resonance (CMR) imaging findings consistent with the diagnosis of hypertrophic cardiomyopathy (HCM). The electrocardiogram, however, showed a QRS pattern resembling an Epsilon wave, a feature of arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole exome sequencing (mean depth of coverage of exons 178X) analysis did not identify a pathogenic variant in the known HCM genes but identified an established causal mutation for ARVC. The mutation involves a canonical splice accepter site (c.2146-1G > C) in the PKP2 gene, which encodes plakophillin 2. Sanger sequencing confirmed the mutation. PKP2 is the most common causal gene for ARVC but has not been implicated in HCM. Findings on echocardiography and CMR during the course of 4-year follow up showed septal hypertrophy and a hyperdynamic left ventricle, consistent with the diagnosis of HCM. However, neither baseline nor follow up echocardiography and CMR studies showed evidence of ARVC. The right ventricle was normal in size, thickness, and function and there was no evidence of fibro-fatty infiltration in the myocardium.ConclusionsThe patient carries an established pathogenic mutation for ARVC and a subtle finding of ARVC but exhibits the classic phenotype of HCM, a contrasting phenotype to ARVC. The case illustrates the need for detailed phenotypic characterization for patients with hereditary cardiomyopathies as well as the challenges physicians face in applying the genetic discoveries in practicing genetic-based “precision medicine”.