Genetic Testing in Brugada Syndrome: Embracing Shades of Gray

Approximately 22 years ago we identified a large family with what is now known as Brugada syndrome (BrS) and used positional cloning to identify mutations in an unstudied gene, GPD1-L, that causes BrS and Sudden Infant Death Syndrome.^1–3 I read with interest the report by Hosseini et al. in Circulation ranking SCN5A as the only definitive BrS gene and classifying all the others as ‘disputed in regards to any assertions of disease causality’.⁴ I will note shortcomings in the data used for classifying GPD1-L and serious concerns regarding the implications of their conclusions on research and clinical care in our field.

For GPD1-L: 1) Our 2007 manuscript linked GPD1-L in 16 affected subjects to a 3.7 cM, not a 15 cM region^1,2,4. 2) We looked for mutations in all genes identified in the linkage region in 2007.² 3) The relatively high (1/5000) GPD1L-A280V variant frequency does not preclude GPD1-L as causative in this family (LOD score >5). There could be linkage disequilibrium with another intronic/intergenic mutation or epigenetic/environmental factors. In addition, cardiac Na⁺ current has a huge safety margin, making it difficult for any single modulator mutation to cause disease with high penetrance. 4) How do Hosseini et al. know there are no families with GPD1-L mutations identified after 2007, as most would not be published? 5) Na⁺ current deficiency causes BrS. The identification of GPD1-L has led to reports that Na_v1.5 is regulated by PKC-mediated phosphorylation, by metabolic factors including NAD⁺ and NADH, and by SIRT1-mediated deacetylation.⁵ All available published and unpublished data should be assembled and weighted appropriately for determining causality.

Hosseini et al. conclude: ‘Routine genetic evaluation of genes other than SCN5A is not currently warranted in the clinical care of BrS patients’.⁴ I disagree. As clinicians, we interpret test results in context. A borderline elevated Troponin means something different in a 50 year old hypertensive diabetic man with chest pain and EKG changes versus a 60 year old with a nonischemic cardiomyopathy and heart failure exacerbation. Exclusion of the 20 potential BrS genes from clinical testing panels will limiting testing for cosegregation and de novo mutations, and slow the determination of causality.

Regarding clinical genetic testing companies, perhaps we should couple payer reimbursement to placing all genetic findings in a public database along with deidentified demographic, family history and clinical data. This would speed discovery and increase transparency.

I am concerned that arbitrary and absolute definitions, when applied in science and medicine, will lead to ill-conceived decisions that limit test availability and stifle research. A classification scheme that ranks 1 gene at the highest and 20 genes at the lowest rank may make a preconceived point, but does little to advance science or clinical care. I applaud Hosseini et al. for their attempt to broach a complex subject that requires thought and consideration. I encourage them, however, to more boldly embrace the gray of the world within which we live.