NEW YORK (GenomeWeb) – Only one of the 21 genes reportedly linked to Brugada syndrome has enough supporting evidence for its inclusion in clinical genetic tests, according to a new analysis.
Brugada syndrome is arrhythmia condition that affects 1 in 2,000 people and can lead to sudden death. More than 20 genes have been reported to be associated with the condition, and many are included on Brugada syndrome gene panel tests.
An expert panel convened by the NHGRI-funded Clinical Genome Resource (ClinGen) evaluated the evidence supporting those genes' links to the syndrome using an evidence-based gene curation framework developed by ClinGen. As the panel reports in the journal Circulation today, it found that the data underpinning nearly all of these genes' inclusion in clinical genetic tests for Brugada syndrome was limited.
"This work highlights the importance of a systematic approach to gene curation as we move from clinical genetic testing in clinically affected individuals to more broadly offering it to asymptomatic individuals," Geisinger Health System's Christa Lese Martin, a ClinGen principal investigator and cochair of the Gene Curation Working Group, said in a statement.
Last year, a ClinGen team, including Martin, presented a framework in the American Journal of Human Genetics to gauge the strength of associations between genes and disease. This semi-quantitative approach relies on both the amount and quality of data to assess the strength of gene-disease pairs and categorize the evidence level as "limited," "moderate," "strong," or "definitive."
Using that framework, researchers led by Toronto General Hospital's Michael Gollob formed three expert panels to independently evaluate 21 genes that are often included in genetic tests for Brugada syndrome. An addition panel of domain experts then conducted a final evaluation and classification of the genes.
All three curation teams concluded there was only definitive-level evidence for SCN5A for Brugada syndrome and that the remaining 20 genes had limited evidence. The domain expert panel then re-classified all the limited-evidence genes as "disputed."
This, the researchers said, challenges those genes' inclusion on gene panel tests.
The disputed genes lacked sufficient data to support their causality in the condition, the researchers said. For instance, they noted that some of the papers supporting their role in disease had insufficient familial or segregation data of affected cases, underestimated the frequency of variants thought to be rare in the general population, or only had functional data from in vitro experiments.
Most of these disputed genes were originally reported in candidate gene studies based on biological plausibility, rather than a familial linkage or genome-wide approach, the researchers noted.
The researchers noted the link between the one definitive-level gene, SCN5A, and Brugada syndrome was originally reported in a candidate gene study, but that additional studies then added to its claim.
There are, the researchers said, practical ramifications to these disputed genes' inclusion on gene panel tests as they could lead to unnecessary testing and treatment. "Diagnostic conclusions in patients and family members or the decision to implant cardioverter defibrillators in otherwise healthy individuals on the basis of findings from the genes with disputed associations could lead to undue harm," Gollob said in a statement.
There are 30 other expert panels performing similar evaluations of disease and gene associations.