Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac entity characterized by right ventricular, or biventricular, fibrofatty replacement of myocardium. Structural alterations may lead to sudden cardiac death, mainly in young males during exercise. Autosomal dominant pattern of inheritance is reported in most parts of pathogenic genetic variations identified. Currently, 13 genes have been associated with the disease but nearly 40 % of clinically diagnosed cases remain without a genetic diagnosis. New genetic technologies allow further genetic analysis, generating a significant amount of genetic data in novel genes, which is often classified as of ambiguous significance. We focus on genetic advances of arrhythmogenic right ventricular cardiomyopathy, helping clinicians to interpret and translate genetic data into clinical practice

Genetic causes of sudden infant death syndrome: a postmortem investigation not to be missed

Sudden cardiac deaths in infancy have always been assumed to be caused by genetic defects in ion channels, given its lack of structural abnormalities. Nevertheless, it is possible that some of the variants listed as putative pathogenic mutations may be innocuous functionally. Therein lies the difficulty in determining the \u201cactionableness\u201d of these rare, nonfunctionally characterized genetic variants when the probability of pathogenicity for that given variant is not 100%. Believe it or not, together with the preliminary hypotheses raised by Harris et al regarding possible novel respiratory viral infections as causes of SIDS, we still do need to account the putative role of HCM genetic variants in SIDS, which lead us a new scenario in diagnosis and prevention of this lethal entity

Further evidence of the association between LQT syndrome and epilepsy in a family with KCNQ1 pathogenic variant

reserved11mixedDe Llano, Coloma Tiron; Campuzano, Oscar; Pérez-Serra, Alexandra; Mademont, Irene; Coll, Monica; Allegue, Catarina; Iglesias, Anna; Partemi, Sara; Striano, Pasquale; Oliva, Antonio; Brugada, RamonDe Llano, Coloma Tiron; Campuzano, Oscar; Pérez Serra, Alexandra; Mademont, Irene; Coll, Monica; Allegue, Catarina; Iglesias, Anna; Partemi, Sara; Striano, Pasquale; Oliva, Antonio; Brugada, Ramo

Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p

We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of Beckwith-Wiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198 kb) also included exons 11-16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita's mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests

Genetic analysis, in silico prediction, and family segregation in long QT syndrome

The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality.European Journal of Human Genetics advance online publication, 26 March 2014; doi:10.1038/ejhg.2014.54