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ACMG Adds Three New Genes to Secondary Findings List

NEW YORK — The American College of Medical Genetics and Genomics (ACMG) has added three new genes to the latest release of its secondary finding list, v3.2. Clinical labs are recommended to report secondary findings on genes catalogued on ACMG's list when conducting clinical exome or genome sequencing.

A paper describing ACMG's decision-making process was published in Genetics in Medicine on Thursday.

The three new entrants on the list are cardiovascular calmodulin genes — CALM1, CALM2, and CALM3. These genes cause predisposition to long QT syndrome, and available evidence supports a similar or greater risk of morbidity and mortality compared with other sudden cardiac death genes that were already in previous versions of the list, the authors noted.

CALM1, CALM2, and CALM3 are located on different chromosomes, but they encode identical 149-amino-acid proteins. All these genes were previously classified by ClinGen as having definitive evidence for LQTS with atypical features such as presentation in infancy or early childhood and with functional heart block and severe QT prolongation, the authors said.

Meanwhile, another gene, ATP7A, was in the running but was ultimately excluded from the list. The authors said that this gene could be reviewed again in the future if new data emerges related to either Menkes disease or other phenotypes associated with ATP7A.

"We continue to balance the goals of providing secondary findings to patients while striving for a minimum list of the most actionable, and impactful, secondary findings," David Miller, lead author on the paper and co-chair of the ACMG Secondary Findings Working Group (SFWG), said in a statement.

The ACMG first issued such a list in 2013. At that time, it recommended that clinical labs, in addition to reporting findings related to why individuals were undergoing sequencing analysis, also report out results found in a set of 56 genes. This included genes involved in hereditary breast and ovarian cancer, hypertrophic and dilated cardiomyopathy, familial hypercholesterolemia, and more. The ACMG further updated this list in 20162021, and 2022, both removing and adding genes.

Cardiovascular genes have been represented on the ACMG secondary finding list since its inception because of the "morbidity and mortality of heart failure and sudden cardiac death, which can both be treated or prevented with well-established interventions," the authors said. 

The ACMG SFWG will continue to review the current list of actionable genes, as well as new nominations throughout the course of the year, the authors said.

The next updated list will be published in January 2024.