“I was in the middle of a sentence when, next thing I know, I wake up on the floor,” she says, but denies any prodrome of dizziness or lightheadedness. Witnesses report no signs of a seizure and say she was unresponsive for about a minute.
She currently has no complaints. Review of systems is negative. She is taking no medications. Her vital signs and her physical exam are both normal.
“Syncope,” you think to yourself, “ECG, beta-hCG, hematocrit.” But as you turn to leave, she says, “I was wondering… some time ago, my mom had me genetically sequenced, and I remember I had a mutation for Brugada syndrome. Let me check.”
She pulls out her mobile device and says, “Yes, I have a mutation called rs41261344 (CT) in the SCN5A gene. They say the information is just for research – for educational and informational use, not medical. But I can’t help wondering whether it might have something to do with me passing out.”
I HAVE A MUTATION IN THE SCN5A GENE CALLED RS41261344.
The Brugada syndrome ECG pattern is characterized by ST segment elevation in leads V1-V3 and right bundle branch block. Of the three types of ECG pattern pertinent to the diagnosis of Brugada syndrome, Type 1, with its coved ST segment that gradually descends to an inverted T wave, is considered the most common. However, each of the three ECG types, when accompanied by at least one of several specific symptoms (including syncope), are regarded as confirmation of the diagnosis.
Although the mean age of sudden death from Brugada syndrome is 40, symptoms can present at any time of life starting from early infancy. The syndrome affects approximately 5 in 10,000 people worldwide, mainly young men of Japanese and South East Asian descent.
What was that rs thing she mentioned?
AN rs NUMBER REFERS TO A SPECIFIC SINGLE NUCLEOTIDE POLYMORPHISM (SNP).
Single Nucleotide Polymorphisms, or SNPs (pronounced “snips”), are the smallest and most common type of genetic variation in the human genome. They occur throughout a person’s DNA. A SNP may, for example, replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA. SNPs can occur within coding sequences of genes, in non-coding regions, or in intergenic regions. Not all SNPs within a coding sequence change the amino acid sequence of the protein that is produced. On average, SNPs occur once in every 300 nucleotides, which means the human genome contains roughly 10 million.
In summary, the rs number helps us keep track of SNPs.
When I search the web for “rs41261344”, all I get is a mess. Where else can I try?
TRY OMIM OR CLINVAR
Go to Online Mendelian Inheritance in Man at www.omim.org and enter “rs41261344” to find out which gene the rs number refers to. In this case, it’s SCN5A, or the cardiac sodium channel gene.
Clicking through to the gene will give you information about many different mutations that have been described on the gene. Searching the page for the rs number will likely take you to a place on the webpage where known research for that specific mutation is linked to in PubMed.
Likewise, searching NIH’s ClinVar (www.ncbi.nlm.nih.gov/clinvar), you can get more information about the SNP, including the potential clinical significance of the SNP based on submissions to the site. In this case, ClinVar reports “Conflicting interpretations of pathogenicity”.
How could I ever use this website stuff?
SEQUENCING DNA AND FINDING VARIATIONS IN AN INDIVIDUAL IS FAIRLY INEXPENSIVE AND FAST. THE EXPENSIVE, TIME-CONSUMING PART COMES WHEN YOU START INTERPRETING THE RESULTS.
One current problem in genomics has been explained as “The $1,000 genome, the $100,000 analysis.” That is, the genomic sequence itself is becoming less and less expensive, but interpreting the results can sometimes be controversial.
For example, in a study reported in JAMA, several labs were given sequences of SCN5A (from a patient who had a mutation) and KCNH2 (which encodes another cardiac ion channel) and asked to classify them as pathogenic or likely pathogenic. Rather worryingly, the findings of the three laboratories coincided only 10% of the time.
Would her unsolicited information change my approach?
A REASONABLE APPROACH TO THIS CASE WOULD BE TO SCRUTINIZE THE ECG AND CONSULT WITH AN ELECTROPHYSIOLOGIST.
As the patient stated, most direct to consumer genomic testing is directed at wellness or research. Ideally, any mutation should be confirmed with a clinical test, however, the turn around time for such tests precludes them from the decision making process in the Emergency Department.
A quick search of OMIM shows that in the literature this gene has been associated with long QT syndrome and Brugada syndrome. Whether or not it actually causes these syndromes is debatable.
At the very least, such information might prompt a clinician to scrutinize the ECG for its corrected QT interval and the Brugada pattern. If the QTc was more than 500 milliseconds or you saw the characteristic Brugada pattern, it would be easier to make a decision.
However, ECG is not the be all and end all of Brugada syndrome, because in some individuals the Brugada pattern occurs intermittently. Therefore, a reasonable approach to this case would be to consult an electrophysiologist.
Brugada EKG from Srivathsan, Komandoor, et al. “Ventricular tachycardia in the absence of structural heart disease.” Indian pacing and electrophysiology journal 5.2 (2005): 106-121. Accessed 2/25/16. (Creative Commons Attribution License)
Mutliple images from unsplash.com
Brugada image from Goraksha, Shwetal, et al. “General anaesthesia for insertion of an automated implantable cardioverter defibrillator in a child with Brugada and autism.” Indian journal of anaesthesia 54.6 (2010): 562. Accessed 2/25/16. (Creative Commons Attribution License)