Introduction
Sudden cardiac arrest (SCA) in young adults is frequently caused by inherited cardiac
diseases, particularly cardiomyopathies and ion channelopathies.
1
Genetic testing can be essential in
the follow-up of survivors and today´s genetic diagnostics may include the parallel
analysis of several SCA related genes, most commonly those associated with ion
channelopathies and hypertrophic cardiomyopathy (HC). We present the case of a young
survivor of SCA, carrier of double heterozygosity for mutations in the
SNC5A and MYBPC3 genes, illustrating the
complexity of genotype-phenotype associations and the difficulties of decisions
regarding therapeutic interventions in inherited cardiac diseases.
Case Report
A healthy 19-year-old man suffered SCA while playing football. His girlfriend (a
medical student) carried out cardiopulmonary resuscitation until the arrival of the
ambulance. Polymorphic ventricular tachycardia degenerating into ventricular
fibrillation (VF) was documented (Figure 1A)
and defibrillation was successfully performed (Figure
1B). At subsequent hospital admission, the electrocardiogram (ECG) showed
sinus rhythm (95 bpm), with a PR interval of 0.26-0.28 sec and a QTc interval of
0.45 sec. (Figure 1C). The echocardiographic
study (echo) was normal and reversible causes of SCA including ionic, infectious and
toxic were excluded. The patient had a normal clinical exam and no personal history
of severe illness. He took no medication. There was no family history of cardiac
disease or sudden death. Thoracic X-ray, cardiac magnetic resonance, exercise test
(treadmill) and coronary angiography were normal.
Figure 1
A: Polymorphic ventricular tachycardia degenerating into ventricular
fibrillation (rhythm strips in sequence); B: Rhythm strip after
defibrillation; C: ECG at hospital admission (PR interval: 0.26-0.28
sec; QTc: 0.45 sec).
Electrophysiological study (EPS) showed a prolonged HV interval (80 ms) and
ventricular stimulation (600 ms cycle - 250-220-220 at RV apex) induced polymorphic
VT with no pulse (successfully terminated by external cardioversion). A provocative
test for Brugada syndrome (BrS) was postponed.
After written informed consent, genetic screening was performed on a panel of 9
genes: MYBPC3, MYH7, MYL2, SCN5A, TNNI3, TNNT2, KCNQ1, KCNH2 and
LQT5. The entire coding regions were tested by PCR and direct
sequencing. We found the mutation c.3622G>T; p.Glu1208* in the
SCN5A gene (NM_198056.2), that was already described in BrS.
Additionally, another sequent variant, c.446C>A; p.Ala149Asp, in the
MYBPC3 gene (NM_000256.3) was detected (Figure 2B). This alteration was reported as
a rare sarcomeric
gene variant in a single case of the offspring cohort of the Framingham Heart Study,
including 1,637 unrelated individuals.
2
Although this single individual did not show alteration of the
left ventricle wall thickness, only one wall segment was measured, without any
further detailed information, thus HC cannot be excluded. Besides, no information
was given whether the index case of this family was also harboring this sequence
variant in MYBPC3.
Figure 2
A: Pedigree of the family. MYBPC3+: harboring the MYBPC3 mutation,
SCN5A+: harboring the SCN5A mutation; B: the MYBPC3 mutation
p.Ala149Asp. Upper lane: healthy individual; lower lane: index
patient.
The p.Ala149Asp mutation in MYBPC3 affects an evolutionarily
conserved amino acid and it was absent in 100 age-matched Portuguese control
samples. Regarding the various in-silico mutation prediction programs, PolyPhen2
(http://genetics.bwh.harvard.edu/pph2/) predicted this alteration as
possibly damaging with a score of 0.65 (sensitivity: 0.87, specificity: 0.91). The
SNPs&Go program (http://snps.biofold.org/snps-and-go//snps-and-go.html) predicted
this variant as disease associated variation (0.696).
Subsequent family analysis showed that the patient´s father was carrier of both
SCN5A and MYBPC3 mutations (Figure 2A). The father was submitted to EPS with
provocative test with flecainide. This test showed negative results. The sister of
our index patient was harboring the SCN5A mutation solely. Because
of the young age, we decided not to perform provocative tests or EPS.
A cardioverter defibrillator (ICD) was implanted in the index patient. Provocative
pharmacological tests were systematically refused by the patient thereafter. Serial
ECGs during hospitalization showed normal patterns except for mild PR prolongation
that persisted also during ambulatory follow up. Family screening (parents and
sister) revealed normal clinics, ECG and echo studies.
Discussion
In the patient presented herein, the persistent prolonged PR interval on serial ECGs
that is explained by a prolonged H-V interval during EPS, the induction of sustained
polymorphic VT during EPS (that had to be terminated by an external DC shock) and
the identification of a pathogenic non-sense mutation in SCN5A gene
(already described as causing an important reduction in sodium currents -
INa)
3
favored the diagnosis
of a loss-of-function sodium channelopathy like BrS or progressive cardiac
conduction disease. These inherited conditions may overlap and can coexist in the
same family and even in the same individual and it was suggested that they may
indeed represent different aspects of the same disease and not separate entities.
However, with no BrS sign on ECG and as the patient refused a provocative test, a
clear diagnosis of BrS was not confirmed.
4
Disease penetrance and expressivity are highly variable in these diseases and the
causal role of SCN5A mutations in BrS is not yet clearly
established. The patient´s father, although with the same mutation, was healthy and
a provocative test for BrS was negative. The young sister of the patient had also
a
normal phenotype although invasive tests were not performed. Additionally, both the
patient and the father are carriers of a missense mutation in the
MYBPC3 gene, one common mutated gene in HC, an
autosomal-dominant inherited disease that may cause ventricular arrhythmias and SCA
mainly in the young. The identified mutation supported the probability of
pathogenicity. In HC carriers of a mutant gene, the phenotype may develop late in
life particularly with MYBPC3 gene mutations. However, under the
"appropriate" trigger, like strenuous exercise as was the case with our patient,
sudden death may be the first manifestation of the disease. To our knowledge, this
is the first report on SCN5A and MYBPC3 double
mutations.
Genetic tools and protocols are evolving fast.
5
The new era of genetic testing, with the easy possibility of
screening a large number of genes, like next generation sequencing, is greatly
enhancing the perspectives of a genetic diagnosis in inherited cardiomyopathies in
a
fast and cost-efficient way. However, it is also increasing the complexity of
interpretation namely in the context of a limited or even absent phenotype, thus
caution should be kept when considering clinical decisions.