Clinically, I was given a dubious diagnosis of Cardiomyopathy. In this case, can the genetic test be useful for defining the diagnosis?
The identification of the genetic mutation is the safest method to confirm the suspicion of Cardiomyopathy, while if the mutation is not identified, the doubt remains and only cardiological checks and possibly more in-depth genetic analyzes will allow to clarify if it is Cardiomyopathy.
What is the use of genetic testing for Cardiomyopathy?
Currently, the clinical usefulness of genetic testing consists in confirming cardiomyopathy in doubtful cases, for example with initial manifestations (eg presence only of typical abnormalities on the ECG). Then to specify the type of cardiomyopathy, for example, in hypertrophic cardiomyopathy, both in children (e.g. Danon's disease) or in adults (Fabry's disease or Amyloidosis). Also to exclude or confirm the presence of the mutation in family members.
The children of a patient with cardiomyopathy must be checked periodically (every 2-3 years in young people and at most 5 years in adults) with ECG and Echocardiogram. However, if a mutation has been identified in the parent, which the child has inherited but without yet showing signs of Cardiomyopathy, the check should be done more frequently (every year for a maximum of 2 years)
Will knowing the mutation allow me to access targeted drug therapies?
Identifying the genetic mutation is very important because in some cases it allows to identify different diseases (eg in the case of hypertrophic cardiomyopathy, Fabry disease or cardiac amyloidosis due to Transthyretin), which can be treated with specific drugs.
In other cases it is less relevant, but in the near future it is expected that drugs or gene therapies will be available that will preventively limit or block the development and progression of Cardiomyopathy.
If the mutation is not identified in the genes most frequently found, does it mean that my cardiomyopathy does not have a genetic basis?
The current genetic analysis involves the use of different types of panels according to the type of Cardiomyopathy.
For example, in hypertrophic cardiomyopathy 8 of the sarcomeric genes can be sequenced, known as the most frequent cause of hypertrophic cardiomyopathy, and 4 other genes, whose mutations are responsible for other cardiomyopathies that appear similar to hypertrophic cardiomyopathy but with manifestations different, which can then benefit from specific therapies. If no mutations are found in the 12-gene panel, the cardiologist may request further investigation and extension of the genetic analysis to more rare genes. However, if it is not possible with current techniques to identify the mutation responsible for Hypertrophic Cardiomyopathy, a genetic cause of Cardiomyopathy cannot be excluded for the moment.
In some laboratories instead of the initial panel of 12 genes, a larger panel of up to 174 genes is used.
If a mutation is identified with the genetic analysis, will this help me know if the cardiomyopathy will get worse later?
It is not currently possible to associate the subsequent course of Cardiomyopathy with certainty to the type of single mutation. If 2 or 3 mutations are identified, even in different genes, the course of cardiomyopathy is usually more severe. But anyway We can only evaluate a degree of probability.
The clinical manifestations of cardiomyopathy associated with the same mutation can be very different in family members, sometimes milder or more severe. Often in other family members who have the same mutation, cardiomyopathy has not yet manifested itself. This variability is defined as "incomplete penetrance". Probably other genes, yet to be precisely identified, have an ameliorative or pejorative effect on the subsequent development of Cardiomyopathy. Instead, it is already established that other elements such as obesity, intense sporting activity, and arterial hypertension can facilitate the development of cardiomyopathy in family members with the same genetic mutation. More rarely it presents itself in a different way (e.g. the father has dilated cardiomyopathy while the son may have hypertrophic cardiomyopathy).
In a recent multicenter international study (Florence, Rotterdam, Boston, Sidney) based on the analysis of over 200 relatives of patients with Hypertrophic Cardiomyopathy, in whom the same mutation had been identified without yet having electrocardiographic or echocardiographic signs of Cardiomyopathy, Hypertrophic Cardiomyopathy developed in only 10% of subjects after a period of cardiological control average of 6 years. (Maurizi N, Michels M, Rowin EJ, Semsarian C, Girolami F, Tomberli B, Cecchi F, Maron MS, Olivotto I, Maron BJ. Clinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy. Circulation 2019).
In the future, only further studies through genetic analyzes and more in-depth cardiological investigations on numerous families will be able to give us more precise answers.
Is it possible that a family member who has inherited the mutation never gets sick?
The identification of a mutation in a subject still without signs of Cardiomyopathy indicates only the chance that, later, Cardiomyopathy may occur, more often between the ages of 40 and 60, but in some cases even after the age of 70. But it is also possible that you never highlight it.
What is the probability of transmission to my children?
The risk of an individual child of a parent with cardiomyopathy inheriting the mutation is usually 50% (“autosomal dominant” inheritance).
In some cases (eg. Fabry or Danon disease cardiomyopathies) the hereditary transmission of the disease is linked to the sex of the parent because the genetic mutation is present in the X chromosome: in these cases the father can transmit the genetic mutation only to the daughters, but not to sons, while the mother can transmit it to both males and females ("X-linked" transmission).
If the child does not have the mutation identified in the parent, is it possible that it will recur in my grandchildren?
If the mutation is not passed on, it cannot reappear in subsequent generations. Not having inherited the mutation means not being able to transmit the Cardiomyopathy due to that disease to future generations. However, there is a possibility that cardiomyopathy may occur in children due to another mutation that genetic analysis was not initially able to identify.
Since I have hereditary cardiomyopathy and the mutation has been identified, can I genetic test my four-year-old son who has had ECG and ECHcardiogram and has no signs of cardiomyopathy?
This is not advisable, as each individual must be free to choose to know or not to know whether he has inherited the mutation. We do not consider it reasonable to let a child know that he is at risk of becoming ill during his life, not knowing how to define the age of onset of the disease or how it will manifest itself, and above all not being able to intervene at least for now to prevent it from developing.
Therefore, as established by the Privacy Guarantor (Official Gazette of the Italian Republic n.159 of 11 July 2011) in the case of minors the genetic test can be carried out only when they are of age, unless the clinical signs of CMI emerge in the meantime or intends to undertake a competitive sporting activity with strong physical commitment.
Now that the genetic mutation that causes my disease is known, would it be possible to see before birth whether it will be inherited in my child?
Cardiomyopathies that occur in prenatal age and at birth are fortunately very rare. Through the techniques of non-invasive prenatal diagnosis (prenatal echocardiography) it is possible to recognize if the thickness and size of the heart chambers have normal or altered dimensions. Prenatal ECHO is recommended and is usually done during pregnancy.
On the other hand, even if it is possible, invasive prenatal diagnosis is not recommended (amniocentesis, CVS to obtain cells of the future unborn child, extract the DNA and then proceed to search for the mutation already known in one of the parents). This is because even if the mutation were identified in the unborn child, in the absence of signs of Cardiomyopathy, we would not be able to know if and when in his life it could lead to the onset of the disease, nor its possible severity. In the same family we can have subjects with the same genetic mutation but without signs of cardiomyopathy even in adulthood.
At the present time it remains to the joint decision of both parents, after genetic counseling, and with the approval of the cardiologist, who must assess the risk of pregnancy in the mother, and of the gynecologist, whether to proceed with procreation.