Genetics and HCM


When learning about HCM you will read that this is a genetic disease, but what does that really mean? To begin to understand genetics a little better we should first understand the basis for genetic knowledge, DNA. In short DNA is what makes YOU what you are. It is defined as the double-stranded, helical molecular chain found within the nucleus of each cell. DNA carries the genetic information that encodes proteins and enables cells to reproduce and perform their functions. Molecular genetics is the field of biology which studies the structure and function of genes at a molecular level. Molecular genetics employs the methods of genetics and molecular biology. It is so-called to differentiate it from other sub fields of genetics such as ecological genetics and population genetics. We have learned a great deal about HCM through the work of many researchers. Today we hope to take these discoveries and use them to assist in the identification of those with HCM.

What do we know about genetics in HCM?

As of August 2017, a multitude of 1000+ mutations in 17+ genes, which are necessary for the development and contraction of heart muscle cells (in units called sarcomeres), have been mapped to their respective chromosomes and isolated from members of families with HCM; (some of these mutations also exist in skeletal muscle, as well as heart muscle).  The 11 most common genes presently regarded as causing HCM are known in scientific terms as: 1) beta-myosin heavy chain; 2) cardiac myosin-binding protein C; 3) cardiac troponin-T; 4) troponin I; 5) alpha-tropomyosin; 6 & 7) essential and regulatory myosin light chains; 8) actin; 9) alpha-myosin heavy chain; 10) titin; and 11) muscle LIM protein.  In most patients, HCM is caused by the initial 3 genes on this list while the other 8 genes each account for only a small fraction of the patients.  Additional genes and mutations responsible for HCM will undoubtedly be identified in the future since the known mutant genes account for only about 60% of the overall patient population. Among these genes more than 500 individual mutations have now been identified. In the past few years a long list of mutations have been identified and suspected to be responsible for HCM in many families, however the numbers and power of this data are still early to know if these mutations are responsible for the 40% of HCM we have yet to find solid genetic causation for.  Indeed, this is one of the reasons HCM is widely regarded as a diverse and heterogeneous disease.  

HCM mimickers

We also know there are other genes that cause conditions that  have a similar appearance to sarcomere mutation related HCM in the heart.  These diseases fall into a few different areas and each have a genetic component that sets them apart from the sarcomere mutation HCM.  In some of these cases the treatment may be similar to that of sarcomere HCM, however others have dramatically different treatments and clinical course thus it is important to know the reason root cause of the changes in the heart.

  1. Glycogen storage disorders – such as Pompe’s disease
  2. Lysosomal storage diseases-  such as Fabry’s and Danon’s disease
  3. Syndromes – such as Noonans, Leopards and Costello’s
  4. Other conditions – cardiac sarcoidosis or cardiac amyloidosis

Because the treatment can vary between the underlying cause of the appearance of HCM it is advised to discuss genetic testing with your doctor.  This is acutely important if the disease is being diagnosed in a young child as many of the non-sarcomere forms of HCM have poor prognosis if not identified and treated early.

What is a mutation?

mutation is a defect in the DNA code, the protein structure of the gene.  These DNA abnormalities may take many forms, but some can be likened to a “spelling error” in the genetic code of DNA such as displacement in the order or sequence of just one of the many amino acids (the individual “building blocks” of the gene protein).  Indeed, it is striking and perhaps surprising that such seemingly minor-appearing abnormalities in the gene sequence can make such a profound difference in the structure of the heart, as occurs in HCM.

Patients often inquire about the cause of their mutation, particularly if the gene abnormality has apparently appeared for the first time in a family (as a de novo mutation).  This consideration usually arises when a newly diagnosed child has both parents with a normal echocardiogram and no evidence of HCM.  Keep in mind that the genetic predisposition to HCM (i.e., the mutant gene) does not always trace back many generations in the same family but may occur spontaneously and for the first time in a member of the most recent generation.  This is known as a de novo mutation.  At present, the environmental factors that may trigger HCM mutations are unknown.



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Foundation for Sarcoidosis  Research website