Genomic Experts Throw Cold Water on Most Long QT Genes

Patrice Wendling

January 28, 2020

Genomics experts say evidence falls short for more than half the genes published and anointed as causing long QT syndrome (LQTS) and assessed routinely on commercial genetic test panels.

Of the 17 genes previously reported in the literature to cause LQTS, nine were classified as having "limited" or "disputed" evidence for a gene-disease association.

Only the three genes first associated with LQTS — KCNQ1, KCNH2, and SCN5A — had "definitive" evidence as a genetic cause of typical LQTS.

Four other genes — CALM1, CALM2, CALM3, and TRDN — had strong or definitive evidence for causing rare cases of infantile/pediatric LQTS with atypical features.

The remaining gene, CACNA1C, had a definitive association with the rare multiorgan condition, Timothy syndrome, but only moderate-level evidence for causing LQTS, the authors report today in Circulation.

"Genes with disputed or limited evidence for causation of LQTS should not be routinely tested for diagnostic purposes in patients with suspected LQTS," senior author Michael Gollob, MD, Toronto General Hospital Research Institute, told | Medscape Cardiology in an email. "Testing genes that lack scientific evidence for disease causation creates a risk of misinterpretation of the genetic information, and potentially an incorrect diagnosis in a patient and their family members."

"Many of us have seen numerous cases of wrongly diagnosed patients based on misinterpreted genetics, many of whom have suffered undue mental health and physical consequences of these errors," he added.

The international team of researchers, part of the National Institutes of Health-funded Clinical Genome Resource (ClinGen) Consortium, performed a similar study in 2018 and shot down all but one of 21 genes reported to cause Brugada syndrome, another genetic arrhythmia disorder with a risk for sudden cardiac death.

"We're really in a phase of needing to do a tremendous amount of clean-up work in genomic medicine, in general, and in genetic cardiology. Because what we used to implicate a gene as a disease-causative gene a decade ago — now in the lens of current knowledge and current dataset — looks to be almost prehistoric," Michael Ackerman, MD, PhD, a genetic cardiologist at Mayo Clinic Rochester, Minnesota, and coauthor of both papers, said in an interview.

Many of the seminal studies for the six disputed (AKAP9, ANK2, KCNE2, KCNJ5, SCN4B, and SNTA1) and three limited-evidence genes (CAV3, KCNE1, and KCNJ2), for instance, were based on a candidate gene approach, which is more likely to yield false-positive results than genome-wide association studies.

Variants were also identified that are now known to be relatively common in certain populations, such as the ANK2 variant p.Glu1458Gly, present in about one in 650 individuals of European descent and one in 400 individuals of Latinx ancestry, the authors report.

The evidence needed to designate a genetic variant as pathogenic has changed dramatically, agreed Dan Roden, MD, PhD, a leader in arrhythmias and pharmacogenomics from Vanderbilt University in Nashville, Tennessee, who was not involved in the study. A decade ago, it was sufficient to find a single proband with a rare genetic disease, like LQTS, who had a nonsynonymous variant that altered the function of a logical candidate gene in vitro.

"We have come to realize that many of those associations don't hold up, for many reasons," Roden said via email. "These include the problems that the in vitro assessments are imperfect and that large sets of sequenced individuals, notably gnomAD, have identified variants that are too common to be labeled as a cause of a rare fatal disease."

Commercial LQTS Testing

As part of the study, the researchers also looked at LQTS genetic panels from 36 labs in North America, Europe, and Australia/New Zealand and found that genes curated as disputed or with limited evidence for LQTS were routinely tested in 83% to 100% of the panels. Only KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were included in every commercial panel.

Given that LQTS is the most common inherited arrhythmia syndrome, affecting about one in 2000 individuals, and genetic testing routine, there will be clinical fallout from the ClinGen findings.

"It's going to be a mess," Ackerman said. "I mean this is the dirty clean-up work where it's going to be a lot of work for genetic counselors and, well, it's going to be a lot of work for those who drank the Kool-Aid and accepted the clinical genetic test result hook, line, and sinker without independently really thinking about it."

At the same time, "the genetic naysayers will say, see I'm just going to go back to doing it the nongenetic way, and that would be like going back to the dark ages and be ignorant on their part," he said.

Although genetic testing companies could easily operationalize the new LQTS findings into their panels, Ackerman observed that changes have yet to be made to genetic tests in the 18 months since the Brugada results were published.

Genetic testing providers have been testing very large panels of genes for many years without much consideration of gene validity for disease, commented coauthor Gollob.

"Our efforts are relatively recent; I would not expect a change in their panels immediately," he said. "However, the ultimate goal of our work is encourage test providers to be responsible in the genes provided on their panels, and to only include genes with evidence for disease.

"Should providers choose to provide data on genes lacking evidence for disease causation, they should clearly label such genes as within the realm of research," Gollob advised. "Test providers that do not make such adjustments in years to come should expect a sustained pressure to do so from all stakeholders, including patient groups, genetic counselors, geneticists, and disease specialists."

Although there was near unanimous consensus on final gene classifications, some of the downgrades are already raising questions, acknowledged Ackerman, whose own genetic discoveries were on the line.

"We need to not get too crazy with the roller-coaster ride," he said. "There are several colleagues already who are incensed and offended that their disease gene, that they first reported, has gotten demoted to a refuted-evidence status and I don't think we should view it that way.

"We should view it as, the gauntlet has been thrown down, so mount the counterevidence to make the case."

For Ackerman, that includes the calcium channel gene, CACNA1C, which he discovered and calls "an irrefutable, take-it-to-the-bank disease gene" but was graded as having only moderate evidence.

Although the overall findings align with a new Mayo Clinic study, even the ClinGen framework used for reappraisal of the evidence is fair game.

"Maybe some of the 'more work' needs to be to fine-tune the method itself to say, if people think it's a definite disease gene, why is the framework we use not calling it as such and how could it be modified," Ackerman said.

Roden also underlined the importance of research and said the results that many of the "rarer" causes of LQTS do not have sufficient evidence will be important for at least two reasons.

"First, it should influence how we use genetic testing for this disease going forward; at this point, clinical screening should probably not use these insufficiently supported genes," Roden said. "Second, it will challenge the field to generate new, more compelling data to definitively support or reject some of the weaker assertions." 

The study was partially funded by the US National Human Genome Research Institute. Gollob is supported by the Canadian Institutes for Health Research. Ackerman is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death in the Young Program. He is also a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical/now Abbott; and shares with the Mayo Clinic a potential equity/royalty relationship with AliveCor. Roden reports no relevant conflicts of interest.

Circulation. Published online January 27, 2020. Abstract

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