Ion Channelopathy Clinic-Sudden Death
Genomics: An Impromptu Diagnosis
Mathew Schmidt1, Nachiket Patel2 and Timothy E Paterick1*
1 Aurora Medical Center Green Bay, USA
2 Banner Medical Center Phoenix, USA
Submission:May 24, 2018;Published: August 06, 2018
*Corresponding author: Timothy E Paterick, Aurora Medical Center Green Bay, USA, Email:[email protected]
How to cite this article: Mathew Schmidt, Nachiket Patel, Timothy E Paterick. Ion Channelopathy Clinic-Sudden Death Genomics:An Impromptu Diagnosis. J
Cardiol & Cardiovasc Ther. 2018; 11(4): 555817. DOI: 10.19080/JOCCT.2018.11.555817
Brugada syndrome (BrS) is an arrhythmogenic disorder often inherited in an autosomal-dominant fashion that is suspected when an Electrocardiogram (ECG) shows type 1 ECG pattern with ST-segment elevation in the right and anterior precordial leads. BrS is a clinical and ECG diagnosis. BrS is not a genetic diagnosis. Patients with BrS have an increased risk of syncope and sudden cardiac death owing to episodic ventricular tachyarrhythmia. The diagnosis of BrS is based on the presence of the type 1 Brugada ECG pattern, which may occur either spontaneously or after provocation tests with sodium channel blockers.
24-year-old male had a salmonella infection presenting with fever and gastrointestinal symptoms of nausea, vomiting and diarrhea that persisted for 48 hours. He went to an urgent care center where during monitoring he had sudden loss of consciousness with ventricular fibrillation requiring cardiopulmonary resuscitation and 200 joules external defibrillation shock restoring sinus rhythm. Post shock it was noted his potassium was 3.2; magnesium 2.1 and troponin peaked at 53 approximately 30minutes after the arrest. His echocardiogram revealed:
a. Normal LV systolic function and wall thickness. LVEF was 57%.
b. Diastolic was functioning normal.
c. The right ventricle was thought to be enlarged with normal systolic function.
d. Normal valve function.
Cardiac cauterization revealed normal coronaries. The drug screen was negative. Patient was taking no medications. He denied smoking, alcohol use or illicit drug use. He had no risk factors for HIV. There was no family history for premature sudden death. Post arrest ECG revealed normal sinus rhythm, PR interval 198msec, QRS 110msec with incomplete RBBB, and QT interval was 350msec with a corrected QT interval of 374msec. Two days
later the ECG showed sinus rhythm at 90 beats per minute with QRS 120msec with nonspecific IVCD pattern with QT interval was 380msec. The t waves were tall with sharp ascending and descending limbs with symmetrical morphology. (Retrospective review suggests type 2 Brugada ECG) . Prior medical history was significant for migraine headaches and acid reflux disease.
Maternal uncle with lone atrial fibrillation identified at age 33 years and required cardio version with subsequent bradycardia requiring permanent pacemaker. Maternal grandmother had a sister that passed away in infancy, reported due to SIDS.
The initial QT interval (369-390msec) was borderline low during early acute post arrest period in the setting of fever and salmonella infection that normalized to 380-400msec range. There are three Brugada ECG patterns (Figure 1). The patient’s initial ECG (retrospectively) revealed a type 2 Brugada pattern (Figure 2 & 3). The patient had normal left heart structure and function and there was a question of RV enlargement by echocardiography. The latter raised a question of ARVD. Cardiac catherization revealed normal coronary arteries. The elevated troponin level raised a concern regarding coronary spasm in the setting of normal coronary arteries without narrowing or plaque.
a. Subunits of the potassium channel (gain of function) or
calcium channel subunits (loss of function).
b. Calcium channel mutations with shorter than normal QT
interval is associated with Brugada type J-point elevation in
the right pre-cordial leads.
c. RV enlargement made genetic assessment covering
cardiomyopathies including ARVD cardio myopathy and LV
d. The putative genomic substrate for Br is: gene: SCN5A,
locus: 3p21, protein: Na channel alpha subunit (NaV1.5). The
diagnosis of BrS requires the type 1 ECG Pattern.
e. The family was informed that the short QT syndrome
(SQTS) is very rare, with only 100 families diagnosed since
2000. There are three genes that have been found associated
with SQTS, and the chances someone with true SQTS would
have a positive genetic test is 15-20%.
The Gene Dx 97 was performed, and no pathogenic variants
were identified. Variants of uncertain significance in 3 genes were
identified in desmin (DESc79G>A< p.Gly27Ser>), desmoplakin
(DSPc4372C>G< p.Arg1458Gly), and sodium channel (SCN5A
c5068-5070delGAC < p. Arg1458Gly>). These are variants of
unknown significance (VUS) and are not known to be associated
with pathogenic or benign outcomes.
The association of genes desmin, desmoplakin, and SCN5A
with arrhythmogenesis is known, but the identified variants are
not related to pathogenicity.
a. The desmin gene encodes for a muscle specific
intermediate filament that is part of a network connecting
myofibers to plasma membrane and mutations have been
described with familial and cardiac myopathy. Review of
the echocardiogram and his physical examination reveal
preserved LV and RV function and no muscle weakness.
b. The desmoplakin gene mutation has been associated
with arrhythmogenic cardiomyopathy and keratosis, such
as palmoplantar keratosis and wooly hair. The patient and
his family members had no skin or hair abnormalities and
no echo features or rhythm disturbance to suggest ARVD
c. SCN5A gene is associated with Brugada syndrome, atrial
fibrillation, long QT and cardiomyopathy but it was felt there
was no sodium channel-related disorder present on the ECG.
(Retrospectively there was a type 2 Brugada pattern).
The initial shorter QT interval during a febrile illness that
normalized suggested this was not a fixed ion channel mutation.
The potassium channel and calcium channel mutations that have
been described with SSQTS were all negative.
One year after initial presentation the patient was admitted
for quinidine loading by the electrophysiology team for recurrent
shocks for polymorphic ventricular tachycardia. While being
loaded with quinidine an ECG was obtained and it revealed the
type 1 ECG pattern solidifying the diagnosis of BrS. Further
investigation revealed his mother had a type 1 ECG pattern. The
mother had no clinical events. Neither the patient’s uncle nor
father had a Brugada type 1 ECG .
SCN5A targeted BrS genetic testing may be useful in patients
in whom it has been established that there is a high index of
suspicion for BrS based upon analysis of the patient’s clinical
history, family history, and expressed ECG or provocative drug
testing ECG phenotype. Drug testing is not mandated in the setting
of an isolated type 2 or type 3 Brugada ECG pattern. Mutationspecific
genetic testing is recommended for family members and
suitable relatives following the identification of a BrS causative
mutation in an index case. Genetic testing is not recommended
in the absence of an index case. BrS is characterized by right
precordial ST elevation, associated conduction delays, potentially
lethal arrhythmias, and a positive history for premature sudden
death. BrS is typically expressed in males in the third to fourth
decade of life. The prevalence of the disease is estimated to be 1
in 5,000 to 1 in 10,000 in Western countries. The prevalence of
clinically silent type Brugada type 1 ECG pattern is likely much
higher [4-6]. Risk stratification is based upon specific ECG patterns
and symptoms and clinical considerations. Syncope and cardiac
arrest put affected individuals at risk for lethal events [5,6].
Treatment of the high-risk subset of patient is ICD implantation.
The yield of SCN5A genetic testing for strong clinical cases is 25%.
Thus, approximately 75% of BrS cases remain genetic in genetic
The diagnosis of BrS is a clinical diagnosis and requires the
type 1 Brugada ECG pattern in combination with unexplained
syncope, family or personal history of premature sudden death.
Genetic testing is not involved in the diagnosis. Genetic testing
is most useful when one member of a family has been clinically
diagnosed with Brugada Syndrome. If the mutation causing the
disease in that person is identified, then the family members
can be tested for the disease with genetic screening. One of
the challenges of Brugada Syndrome is that ECGs findings are
equivocal, or the pattern can come and go. A Type 2 or 3 Brugada
Pattern, even in the setting of symptoms, is not sufficient to make
the diagnosis. If a patient has a Type 2 or 3 Brugada Pattern, several
maneuvers, such as moving the ECG leads higher in the chest can
change the ECG to a classic Type 1 pattern. However, many times
it is necessary to give these patients intravenous sodium channel
blockers too turn the ECG into a more classic Type 1 pattern. The
medications that are often used are flecainide or procainamide.
In our case treatment with an intravenous sodium channel
blocker led to the fortuitous development of a type 1 Brugada ECG
pattern solidifying the diagnosis of BrS. The patient fell into the
75% of BrS cases remaining in genetic purgatory. Often the key
to diagnosis is careful ECG inspection. In our case the pursuit of
genetic testing was debatable. Given the initial Type 2 Brugada
ECG in a setting od sudden death it would have been prudent to
obtain an ECG with the right precordial leads place one or two
intercostal spaces higher and to consider intravenous sodium
channel blocker in search of the Type 1 pattern to solidify the
diagnosis of BrS. Once the diagnosis of BrS was made then it
would be prudent to pursue genetic testing in the index case. If
gene positive then family member should be encouraged to have