New Variant in Placophilin-2 Gene Causing Arrhythmogenic Myocardiopathy.

INTRODUCTION: Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by progressive fibroadipose replacement of cardiomyocytes. Its diagnosis is based on imaging, electrocardiographic, histological and genetic/familial criteria. The development of the disease is based mainly on desmosomal genes. Knowledge of the phenotypic expression of each of these genes will help in both diagnosis and prognosis. The objective of this study is to describe the genotype-phenotype association of an unknown PKP2 gene variant in a family diagnosed with ACM. METHODS: Clinical and genetic study of a big family carrying the p.Tyr168* variant in the PKP2 gene, in order to demonstrate pathogenicity of this variant, causing ACM. RESULTS: Twenty-two patients (proband and relatives) were evaluated. This variant presented with high arrhythmic load at an early age, but without evidence of structural heart disease after 20 years of follow-up, with low risk in predictive scores. We demonstrate evidence of its pathogenicity. CONCLUSIONS: The p.Tyr168* variant in the PKP2 gene causes ACM with a high arrhythmic load and with an absence of structural heart disease. This fact emphasizes the value of knowing the phenotypic expression of each variant.

Sudden cardiac death in persons aged 50 years or younger: diagnostic yield of a regional molecular autopsy program using massive sequencing.

INTRODUCTION AND OBJECTIVES: Sudden cardiac death (SCD) in young people often has a genetic cause. Consequently, the results of "molecular autopsy" may have important implications for their relatives. Our objective was to evaluate the diagnostic yield of a molecular autopsy program using next-generation sequencing. METHODS: We performed a prospective study of a cohort of consecutive patients who died from nonviolent SCD, aged ≤ 50 years, and who underwent molecular autopsy using large panels of next-generation sequencing, with subsequent clinical and genetic family screening. We analyzed demographic, clinical, toxicological, and genetic data. RESULTS: We studied 123 consecutive cases of SCD in persons aged ≤ 50 years. The incidence of SCD was 5.8 cases/100 000 individuals/y, mean age was 36.15±12.7 years, and 95 were men (77%). The cause was cardiac in 53%, unexplained SCD in 24%, toxic in 10.6%, and infant SCD in 4%. Among cardiac causes, ischemic heart disease accounted for 38% of deaths, arrhythmogenic cardiomyopathy for 7%, hypertrophic cardiomyopathy for 5%, and idiopathic left ventricular hypertrophy for 11%. Genetic analysis was performed in 62 cases (50.4%). Genetic variants were found in 42 cases (67.7%), with a mean of 3.4±4 genetic variants/patient, and the variant found was considered to be pathogenic or probably pathogenic in 30.6%. In unexplained SCD, 70% showed some genetic variant. Family screening diagnosed 21 carriers or affected individuals, 5 of whom were at risk, indicating an implantable cardiac defibrillator. CONCLUSIONS: Protocol-based and exhaustive study of SCD from cardiac causes in persons aged ≤ 50 years is feasible and necessary. In a high percentage of cases, the cause is genetic, indicating the existence of relatives at risk who could benefit from early diagnosis and treatment to avoid complications.

The R820W mutation in the MYBPC3 gene, associated with hypertrophic cardiomyopathy in cats, causes hypertrophic cardiomyopathy and left ventricular non-compaction in humans.

BACKGROUND: The R820W mutation in the MYBPC3 gene has been associated with the development of hypertrophic cardiomyopathy (HCM) in rag-doll cats, but had not been described in humans. AIMS: To describe the phenotype associated with the R820W mutation identified in a human family. METHODS: The R820W was identified by direct sequencing of the MYBPC3 gene in a 47 year old woman with HCM and left ventricular non-compaction (LVNC). Clinical and genetic studies of the R820W mutation were performed in her family. RESULTS: The index patient was homozygous for the mutation and had no additional mutations in the main sarcomeric genes (MYH7, TNNT2, TNNI3, and TPM1). She had HCM with LVNC and normal systolic function. One brother had died suddenly at age 43 years. Another brother diagnosed of LVNC with severe systolic dysfunction and a cardiac arrest was also homozygous for the mutation. One heterozygous 31 year old sister, and three heterozygous sons of the index (ages 14, 20 and 23 years old) were clinically unaffected. The father of the index was apparently healthy and her mother had atrial fibrillation and an electrocardiographic diagnosis of left ventricular hypertrophy at age 86 years. CONCLUSION: The R820W mutation in the MYBPC3 gene, previously associated with HCM in rag-doll cats, causes both HCM and LVNC in homozygous human carriers, with mild or null clinical expression in heterozygous carriers.