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Several Genes Linked to Long QT Syndrome May Not Be Causative, Reappraisal Finds

NEW YORK – More than half the genes thought to be involved in long QT syndrome are not supported by sufficient evidence as causative, a new analysis has found.

Seventeen genes have been linked to long QT syndrome, which is characterized by sudden, irregular heart rhythms. These arrhythmias often, but not always, follow stress or exercise and can be fatal.

A panel convened by the Clinical Genome Resource (ClinGen) has now re-examined the evidence linking these genes to long QT syndrome. As the panel reported Monday in the journal Circulation, it found that only three of the 17 genes have strong evidence for their connection to the common form of the condition and four genes had evidence linking them to atypical long QT syndrome. According to the authors, many of the other genes should not be considered when pursuing genetic testing for long QT syndrome because of their tenuous link to the disease.

"Our study highlights the need to take a step back and to critically evaluate the level of evidence for all reported gene-disease associations, especially when applying genetic testing for diagnostic purposes in our patients," senior author Michael Gollob from the Toronto General Hospital Research Institute said in a statement. "Testing genes with insufficient evidence to support disease causation only creates a risk of inappropriately interpreting the genetic information and leading to patient harm."

Long QT syndrome was first described in the late 1950s, and two genes — KCNH2 and SCN5A — were first linked to the condition in 1995. Since then, additional variants have been associated with the disease and have enabled genetic testing to become part of how long QT syndrome is evaluated within families.

At the same time, additional studies have found that gene variants initially thought to be rare may actually be common. Because of this, ClinGen has aimed to use a standardized approach to evaluate reported gene-disease associations.

Three gene curation teams independently assessed each of the 17 genes associated with long QT syndrome to classify the evidence linking them to the disease as either definitive, strong, moderate, or limited. A working group then reviewed those teams' assessments to come to a consensus and assign the genes' final classifications.

Only three genes — KCNQ1, KCNH2 and SCN5A — were classified as having definitive evidence linking them to typical long QT syndrome, as their association was supported by linkage analyses in multiple families, as well as genetic and experimental evidence.

Four other genes — CALM1, CALM2, CALM3, and TRDN — had definitive or strong evidence linking them to atypical forms of long QT syndrome, such as ones that present in early childhood, often alongside other symptoms such as seizures and developmental delay.

The evidence linking six genes to long QT syndrome was classified as disputed. For four of these genes, the publications linking them to the condition described candidate gene approaches that the curation teams gave less weight, while the evidence linking the other two genes came from linkage analyses in large families that the researchers said had significant limitations.

Other genes had limited evidence for causing long QT syndrome and may instead predispose people to acquiring the condition when there is another precipitating factor, like medication.

The researchers cautioned that genetic testing of genes with limited or disputed evidence for causing disease should not be routinely conducted. They noted that between 83 and 100 percent of long QT syndrome-specific gene panels offered by three dozen genetic laboratories in North America, Europe, Australia, and New Zealand include genes with disputed or limited evidence linking them to disease.