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Different phenotypes in the same family: how genetic studies can help us?

The clinical case of the month: September 2009

Case Presentation

A 50 year old man was admitted due to atypical chest pain not effort related, beginning four days before. He did not have coronary risk factors. Mild systolic murmur was heard on physical examination.

Myocardial Disease

ECG showed sinus rhythm, pathologic Q waves in DI, aVL and V3 to V6, with normal repolarisation pattern (fig. 1). Coronary angiography was normal. His echocardiogram showed asymmetrical septal hypertrophy (maximum 17 mm at basal and medium septum), elongated mitral leaflets and cordal system without SAM; left ventricular ejection fraction was normal and pseudonormal pattern was present on diastolic function assessment (Fig. 2). Cardiac MRI confirmed hypertrophic cardiomyopathy diagnosis, showing maximum wall thickness of 19 mm at basal infero-septal segment (Fig. 3).



Stress test and 24-hour Holter ECG were normal. He was treated with beta-blockers and remained asymptomatic. After informed consent, blood sample was taken for genetic test. A heterozygous frameshift mutation was detected in myosin binding protein C gene (MYBPC3): K600fs, Del A 12413. This mutation has been previously associated with hypertrophic cardiomyopathy. It was detected in only one patient from a French cohort of 197 unrelated index cases. Authors did not provide familial data. Mutated residue was conserved among species and isoforms. Moreover, this genetic variant was absent in 100 healthy adult controls1.

Clinical and genetic screening was performed on first degree relatives. (Fig. 4. Pedigree)


Fig. 4. Black symbols: phenotypic affected subject. White symbols: healthy subjects. ?: subject without clinical and genetic study. +: mutation carrier. -: no mutation carrier. Arrow indicates index case.


His 15 year old daughter (subject II:2) had a normal ECG (Fig. 5) and her echocardiogram showed apical and posterior hypertrabeculation areas that met left ventricular non compaction cardiomyopathy criteria (Fig. 6). Genetic analysis demonstrated that she was also K600fs mutation carrier.

Then we examined the other two siblings. Ten year old son (II:3) had left ventricular hypertrophy criteria on ECG (Fig. 7) and his echocardiogram showed apical and posterior hypertrabeculation areas too (Fig. 8). However he was not carrier of K600fs mutation. Twenty-four year old daughter neither was genetically affected, her echocardiogram was normal and ECG was suggestive but not diagnostic of left ventricular hypertrophy (Fig. 9).

Question with regard to this case:

1. What is your interpretation about K600fs mutation behaviour in this family? Is K600fs mutation the real genetic cause of the disease?
2. Could K600fs mutation have a heterogeneous phenotypic manifestation in the two carriers?
3. Apparently, this mutation does not cosegregate in some family members. Could genetic test have a false negative result in the clinically affected son?
4. What would be your next attitude?

Diagnosis, case resolution and treatment

1. What is your interpretation about K600fs mutation behaviour in this family? Is K600fs mutation the real genetic cause of the disease?
Our answer: K600fs should be considered the cause of the disease in the affected carriers.
Besides the patient with HCM associated with this mutation described in the literature, our group has additional clinical data of 8 families with the K600fs mutation in the MYBPC3 gene. All those families come from Pontevedra, a province of Galicia in the northwest of Spain. The mutation cosegregates with the disease in the 8 families. There are 21 carriers of the mutation and penetrance is nearly 90% in subjects older than 30 years old. Average maximal wall thickness is 20 mm and only two cases have more than 30 mm (one of them with a second mutation). Most carriers are in NYHA functional class II. Left atrial enlargement and atrial fibrillation were common, especially in those carriers who had been practice competitive sports. Consequently, two mutation carriers younger than 55 year old suffered ischemic strokes.
We used BLAST program to assess predicted functional consequences of K600fs mutation. This analysis predicted a stop codon that leads to protein C truncation on amino acid 601 with the consequent lost of C4 and successive domains. Moreover, this mutation was absent in 323 healthy adult controls (100 from the literature1 and 223 from our own investigation).
This information strongly supports the association of the K600fs mutation with the development of hypertrophic cardiomyopathy.

2. Could K600fs mutation have a heterogeneous phenotypic manifestation in the two carriers?

Our answer: It could be, but there may be other explanations.
The index patient has asymmetric septal hypertrophy comparable to the phenotype that we have identified in multiple carriers from other families. However, the phenotype of the second carrier (one of his daughters) is different, without left ventricular hypertrophy but with apical hypertrabeculation. The absence of the typical hypertrophy may be explained by the age of the patient and delayed onset of the disease expression. The presence of apical trabeculation may have three explanations: a) It is a normal variant, b) Is a different phenotypic manifestation of the K600fs mutation, c) It has a different cause, which may be a second mutation in the family. We do not think that it is within the normal spectrum for a Caucasian young woman.

3. Apparently, this mutation does not cosegregate in some family members. Could genetic test have a false negative result in the clinically affected son?

This question is connected with the previous. We initially considered that the son of the index was clinically affected because of the presence of apical trabeculation, but he did not have hypertrophy in other segments. We confirmed that he did not carry the K600fs mutation. As in his father, apical trabeculation was not present in other carriers of the K600fs mutation from 8 different families. Thus we suspected that there are two different phenotypes in this family: HCM and apical trabeculation. The absence of the mutation in the son that did not have hypertrophy does not exclude the cosegregation of the K600fs with HCM in the family. K600fs did not cosegregate with the apical hypertrabeculation.

4. What would be your next attitude?
Our answer: See the mother!
We suspected the presence of two different phenotypes in the family explained by the presence of other genetic factor associated with the development of apical hypertrabeculation.  Proband’s wife clinical assessment was done (subject I:2). Her physical exam and ECG (Fig. 1) were normal. The echocardiogram showed normal wall thickness in the basal and mid-left ventricular segments but prominent trabeculations in the apical posterior, inferior and lateral walls were detected (Fig. 2 and 3).


Notes to editor

Dr. Martín Ortiz, Dr. Roberto Barriales-Villa, Dr. Lorenzo MonserratRichard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, et al.  Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;107:2227-2232

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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