Genomic testing for hypertrophic and dilated cardiomyopathies (HCM & DCM) – 48 genes NGS panel

Cardiomyopathies, or heart muscle diseases, are a common cause of heart failure, which is a leading cause of death in most societies. There are several different types of cardiomyopathy, many of which can have a hereditary cause. The two major types of cardiomyopathy are dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Many different genetic causes of cardiomyopathy have been discovered and identifying the underlying genetic cause can influence medical management decisions and preventive screening options for at-risk relatives. Careful consideration of the personal and family history should be given when deciding which cardiomyopathy panel is most appropriate for testing in an individual patient or family.

Determining the genetic cause of cardiomyopathies can be complex. There have been many different genes and many different mutations involved in inherited predisposition to cardiomyopathy. The genetic cause is further complicated because there is significant phenotypic overlap between the different types of cardiomyopathy and also significant overlap in the genetic causes between subtypes. For example, at least 19 genes have been implicated in both HCM and DCM, and occasionally a person who initially had HCM, may not be diagnosed with heart disease until the disease is very advanced and presents as DCM. In addition, different types of cardiomyopathy can run in families. Some families present with exclusively one type of cardiopmyopathy, such as HCM, whereas in another family we might see the same genetic alteration causing different types of cardiomyopathy in different family members, such as DCM and HCM. Due to this overlap in genetic causes and in the symptoms and presentation of disease for different types of cardiomyopathy, a clinician may consider testing for genes associated with multiple subtypes of cardiomyopathy in one comprehensive test.

Has an estimated prevalence of 1/500 and is characterized by left ventricular hypertrophy (LVH), myocyte disarray and fibrosis. The age of onset ranges from childhood to early adulthood. Mutations in several genes have been implicated in HCM with mutations in MYH7 and MYBPC3 accounting for 60-80% known genetic cause. Genes implicated in HCM primarily encode sarcomeric proteins. Syndromic and non-syndromic genetic forms of HCM have been observed, and in approximately 2-5% of cases, multiple mutations have been observed.

Is characterized by left ventricular enlargement (LVE) with normal wall thickness and systolic dysfunction with an ejection fraction (EF) less than 45-50%. The prevalence of DCM is estimated to be ~1/2700, although this may be an underestimate. Ischemic heart disease is the most common cause of DCM, accounting for approximately half of all cases. Of the remaining non-ischemic DCM cases, approximately 20-35% of cases present with a family history. Genetic causes have been identified in familial and sporadic forms of non-ischemic dilated cardiomyopathy, with several genes implicated in hereditary causes of DCM. Mutations in three genes (LMNA, MYH7, andTNNT2) have been identified in at least 15% of cases, with mutations in additional genes cumulatively accounting for another 10-20% of genetic cause, including genes that encode sarcomeric, nuclear, cytoskeletal-membrane, z-disk and mitochondrial proteins. Mutations in the majority of genes associated with DCM are non-syndromic, although several genes can also be associated with syndromic conditions.

Generally, the majority of cardiomyopathies are expressed and inherited in an autosomal dominant manner, which means that individuals with a mutation in only one of the two copies of a gene have a particularly high risk of manifesting the disease and all first-degree relatives of a patient have a 50% risk of inheriting the disease. It is also important to bear in mind that different mutations in the same gene can lead to the expression of different types of a cardiogenetic disease.

Recently, the introduction of Next Generation Sequencing (NGS) technology has become a highly effective diagnostic strategy, through the parallel analysis of a large number of genes associated with all known types of cardiomyopathies.

InterGenetics has developed and offers an NGS panel for the genomic analysis of all 48 genes, associated with a wide spectrum of cardiomyopathy diseases, irrespective of the mode of inheritance.

We perform DNA sequence analysis, via Next Generation Sequencing (NGS) on a Genome Analyzer – Ion Proton platform, of all exons and intron-exon junctions/splice sites of the 48 genes, allowing us to detect >98% of all pathogenic mutations of the genes through the use of specially developed bioinformatics tools, thus providing in a single step an increased clinical sensitivity and performance compared to single gene testing.

Where possible and/or necessary, we carry out additional MLPA analysis in order to detect deletions/duplications of the genes (please consult the final test report).

The test is highly sensitive and complex, so it is necessary that the results are assessed by a specialized team of clinical and molecular geneticists, in order to ensure safe and reliable testing.

Proper clinical genetic assessment and genetic counseling, both before and after testing, is essential in order to determine the optimum testing strategy and also to communicate properly the concepts of pathological and normal.

See also genomic testing for hypertrophic and dilated cardiomyopathies (HCM & DCM) 33 genes NGS minimal panel