Clinical utility of genetic tests for inherited hypertrophic and dilated cardiomyopathies

Abstract

Genetic testing has become an increasingly important part of medical practice for heritable form of cardiomyopathies. Hypertrophic cardiomyopathy and about 50% of idiopathic dilatative cardiomyopathy are familial diseases, with an autosomal dominant pattern of inheritance.Some genotype-phenotype correlations can provide important information to target DNA analyses in specific genes. Genetic testing may clarify diagnosis and help the optimal treatment strategies for more malignant phenotypes. In addition, genetic screening of first-degree relatives can help early identification and diagnosis of individuals at greatest risk for developing cardiomyopathy, allowing to focus clinical resources on high-risk family members.This paper provides a concise overview of the genetic etiology as well as the clinical utilities and limitations of genetic testing for the heritable cardiomyopathies.

Figure 1

Single gene disorders or complex traits. A single rare mutation can fully account for a Mendelian disease; clinical variability can be, however, observed even for determined monogenic disease, and this variability may itself involve genetic factors, the so-called modifier genes. In contrast to monogenic traits, complex traits have many contributing genes and non-genetic influences.

Figure 2

Autosomal and X-linked patterns of inheritance. In autosomal dominant inheritance, family history typically reveals that the disorder is usually present in every generation, and there is a 50% chance of inheriting the mutation. In autosomal recessive inheritance, the condition appears to "skip" generations. Parents of an affected have a 25% chance of having an affected child and a 50% chance of having a carrier child in each pregnancy. In X-linked dominant inheritance, all daughters of an affected man are affected, sons and daughters of carrier women have a 50% risk of being affected. In X-linked recessive inheritance, there is a 50% chance that each son of a carrier woman will also be affected. No male-male transmission is observed.

Figure 3

Potential guidelines for genetic test selection in inherited hypertrophic cardiomyopathy.

Figure 4

Schematic representation of the genomic organization of the LMNA gene and localization of most prevalent LMNA mutation hot spots. Exon 11 and part of exon 12 encode for lamin A (664 aminoacids) while the alternatively spliced part of exon 10 encodes for the lamin C (572 aminoacids) isoform.

Figure 5

Flow chart showing the clinical management and the genetic counselling for the heritable cardiomyopathies by a specialised cardiogenetic team.