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Sporadic DCM and genetic counselling

A 42-year-old man with a diagnosis of dilated cardiomyopathy was addressed for genetic counselling. Diagnosis was made 3 years before, because of dyspnoea NYHA II. Clinical examination was unremarkable. ECG was performed during sinus rhythm (see Figure 1). Echocardiography exhibited enlarged left ventricle (LVEDD: 61 mm), normal wall thickness (MWTd: 9 mm), depressed systolic dysfunction (LVEF: 30%), enlarged left atrium (LA: 44 mm), mild mitral regurgitation (MR: 2/4) and normal systolic pulmonary artery pressure (sPAP: 30 mmHg). Etiological screening was normal (including coronary artery angiogram). Family history did not reveal any cardiomyopathy or premature sudden cardiac death. The patient has 3 children (16, 15, 11 years). 
Myocardial Disease


Which genetic counselling do you propose to this patient? Do you propose genetic testing?

One year later, the daughter (17 year-old) of the patient died suddenly and unexpectedly after a basket-ball training session. She had no cardiac history but no cardiac examination was performed before the sudden death. Necropsic analysis was performed and revealed a diagnosis of Hypertrophic cardiomyopathy, based on macroscopic (heart weight: 325 g: above expected weight for age, sex and weight, IVS 28 mm) and microscopic (myocardial disarray and fibrosis) features. The father came to the genetics department.
 

What is your interpretation of the cardiac disease(s) in this family?
Which further investigation and genetic counselling would you suggest?

Post mortem examination was performed in the daughter and revealed an heterozygous mutation (Arg102Gln) in the troponin T gene mutation (a mutation previously reported as responsible for HCM). Genetic testing was then performed in the father, and the mutation was also present. Genetic testing was proposed to the siblings (no symptom), after specific genetic counselling multidisciplinary consultation. ECG of the younger brother (12 years at that moment) is in Figure 2. Echocardiography was normal. This brother carried the mutation.



Which management do you suggest for the 12 year-old boy?


ECG with DCM

Figure 1. ECG of the patient with DCM





ECG of the youngest brotherFigure 2. ECG of the young brother (12 year old)


Family pedigree

Figure 3. Pedigree of the family




The resolution

A 42-year-old man with a diagnosis of (sporadic) dilated cardiomyopathy was addressed for genetic counselling.

1/ Which genetic counselling do you propose to this patient? Do you propose genetic testing?

At that stage, DCM was considered as a sporadic disease without any “red flag” that could be suggestive of a specific inherited or non-inherited cause. Information was given about the possibility of a genetic origin, as well as other non-genetic origin. Genetic testing was not performed because of the very low yield of genetic testing in this group of “sporadic” DCM (≤ 10%) but a systematic cardiac screening (with ECG and Echocardiography) was
proposed in all first degree-relatives in the family.

2/ One year later, the daughter (17 year-old) of the patient died suddenly and necropsic analysis revealed a diagnosis of Hypertrophic cardiomyopathy

What is your interpretation of the cardiac disease(s) in this family?
Which further investigation and genetic counselling would you suggest?

DCM in the father was interpreted as a late stage of a possible HCM, that is known as a “burn-out phase” of HCM with remodelling and thinning of wall thickness as well as enlarged LV diameter and systolic dysfunction. The early stage of HCM phenotype could have been missed. Another interpretation is a possible variable cardiac expression of a given mutation. The cardiac disease present in the family was considered as HCM and genetic counselling was given accordingly: autosomal dominant inheritance was explained as well as possible delayed cardiac expression and the potential benefit of cardiac screening in the family. Post mortem frozen tissue sampling was sent to our lab for genetic testing. Molecular analyses were performed first in this deceased girl as she is the propositus with a well characterized phenotype.

3/ Post mortem examination revealed an heterozygous mutation (Arg102Gln) in the troponin T gene. The mutation was also present in the father, and the youngest brother (12 years at that moment).

 Which management do you suggest for this 12 year-old boy ?

This case illustrates the usefulness of post mortem genetic analyses that lead to the correct molecular diagnosis, and subsequently allow appropriate predictive genetic testing in the family members according to a cascade genetic strategy. Predictive testing was proposed to the 12 year-old young brother because of a meaningful risk of cardiac expression and complication at that age, and because of abnormal ECG (deep Q wave, 4 mm in D1 & VL, negative T waves in D1, VL, V4 to V6). Echocardiography was normal. There was no symptom. The management is difficult in this situation as there are no consensual recommendations. There is a very small risk of sudden death before occurrence of LV hypertrophy on echocardiography but some marginal cases have been described, especially in the context of a cardiac troponin T gene mutation. Holter ECG was recommended, as well as exercise testing, to complete the risk stratification. No abnormalities were found. Sport activities were restricted and close cardiac follow-up was planned. No medical treatment or ICD was proposed at that stage as we don’t know precisely the risk of sudden death. This risk is probably very low and does not balanced with short term and long term complications of ICD implantation.

Notes to editor


Dr Philippe Charron, Dr Paul Fornes, Dr Pascale Richard.
« Centre de référence Maladies cardiaques héréditaires », Hôpital Pitié-Salpêtrière & Université Paris 6, France.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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