Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death

Abstract

Sudden cardiac death is defined as an unexpected decease of cardiac origin. In individuals under 35 years old, most of these deaths are due to familial arrhythmogenic syndromes of genetic origin, also known as channelopathies. These familial cardiac syndromes commonly follow an autosomal dominant pattern of inheritance. Diagnosis, however, can be difficult, mainly due to incomplete penetrance and variable expressivity, which are hallmarks in these syndromes. The clinical manifestation of these diseases can range from asymptomatic to syncope but sudden death can sometimes be the first symptom of disease. Early identification of at-risk individuals is crucial to prevent a lethal episode. In this review, we will focus on the genetic basis of channelopathies and the effect of genetic and non-genetic modifiers on their phenotypes.

Penetrance and expressivity of the R858H CACNA1C variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

“…Or, and perhaps more plausibly, might there be an agency of genetic variation at other loci? “Normal variation”—that is, a minor allelic form at another locus or loci insufficient per se to influence channel function—could plausibly comprise a subtle “second hit” effect in the vulnerable setting of a major known pathogenic mutation (Coll et al, ; Giudicessi & Ackerman, ). Such variation would not be expected to co‐segregate with the major mutation; at least with respect to the 14 channel genes listed above, none are located on the same chromosome (number 12) as is CACNA1C .…”

“…Variation elsewhere in the same gene may not, however, necessarily have an effect, as Crotti et al () show with respect to the KCNQ1 (LQTS 1) variant. Other proposed modifying factors, including gender and dietary practice, are reviewed in Giudicessi and Ackerman (), Coll et al (), and Liu et al ().…”

Practical Aspects in Genetic Testing for Cardiomyopathies and Channelopathies

“…48 Most are inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity, yet male patients appear to have a more severe phenotype and higher risk of sudden cardiac death, most probably related to hormonal effects. 49,50 More than 40 genes have been associated with susceptibility to various channelopathies, while variants in the same gene could cause multiple phenotypes. 7,51 Overlap syndromes have been described, in particular related to certain well-characterised SCN5A variants.…”

Modelling of Genetic Cardiac Diseases

“…Another convoluting factor that hinders the genotype-phenotype correlation is variable expressivity within one phenotype because some mutation carriers display all the phenotypic symptoms, whereas some only display part of mutation-specific phenotypes [8]. The clinical heterogeneity of genetic cardiac diseases suggests that ultimate disease severity (i.e., penetrance and expressivity) does not solely depend on one particular gene causing cardiac disease, but instead results from the combination of many modifying factors such as age, gender, and environmental and lifestyle factors, which either exacerbate or protect against disease [9]. In addition, patients carrying more than one disease-causing mutations (i.e., not polymorphisms) either in the same gene or different genes yield to more severe clinical disease including earlier onset of disease, early heart failure, and premature SCD [10].…”