The ACMG update of secondary findings adds to the gene list five genes, including one linked to heart failure


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The American College of Medical Genetics and Genomics (ACMG) has released an update of its recommended minimum gene list for secondary outcome (SF) reporting. In 2021, the ACMG Board of Directors and the Secondary Results Working Group (SFWG) announced that the college would update the roster (SF v3.0) annually. Today’s update (SF v3.1) adds five new genes – four linked to a predisposition to dilated cardiomyopathy and one linked to hereditary transferrin amyloidosis, a cause of heart failure.

The paper “ACMG SF List v3.1 for Reporting Secondary Findings in Clinical Exome and Genome Sequencing: An American College of Medical Genetics and Genomics (ACMG) Policy Statement” represents the work of the expanded SFWG since the last update, with the addition of one bioethicist and one in disorders genetics in diverse populations. The paper is published in the official journal of the ACMG, Genetics in medicine.

said lead author and co-chair of the ACMG SFWG, David T. Miller, MD, Ph.D., FACMG.

Christa L. Martin, Ph.D., FACMG and Co-Chair of the SFWG added, “We recognize that ethical issues are important in genomics and diversity is also an ongoing priority for the College, so we have added two new members to the SFWG, one with expertise in biomedical ethics and another with expertise in genetic disorders in Diverse population groups. Their contributions have been instrumental in this update.”

Guidance from the original ACMG Policy Statement on Incidental Findings (later updated to the current term, “secondary”) in 2013 established that clinical laboratories performing exome or genome sequence A ‘minimum list’ of known pathogens or predicted disease-causing variants in a specific set of genes considered medically actionable, even when not related to the primary medical causes, must be reported for testing. In May 2021, ACMG’s SFWG released the “ACMG SF List v3.0 for Reporting Secondary Findings in Clinical Exome and Genome Sequencing: A Policy Statement of the American College of Medical Genetics and Genomics,” which included 73 genes and was the most cited article published by ACMG last year.

ACMG SF v3.1 adds five genes

While cardiovascular genes were represented in the SF list since its first replication due to morbidity and mortality from heart failure (HF) and sudden cardiac death (SCD), for SF v3.1, the SFWG voted to include four additional genes associated with expansion. Predisposition to cardiomyopathy (DCM): TNNC1, RBM20, BAG3, and DES. The decision is based on evidence that all four genes significantly predispose individuals to DCM at a similar or higher level of morbidity and mortality risk as other DCM genes already included in previous iterations of the list.

The fifth and final gene added to the SF v3.1 list is TTR (transteritin). The TTR was previously reviewed by the SFWG for TTR-associated amyloidosis but was not included in the SF v3.0 list, and the TTR has been reconsidered and included in this update due to the availability of new data on population prevalence and FDA-approved therapies.

In its discussion on TTR, the SFWG found subtle differences regarding the application of its specific criteria in the context of the genetic variants most common in strain groups that are under-represented in genomics research. The SFWG considered comments provided by the community that noted that hereditary transferrin amyloidosis (hATTR) shares a number of traits with hereditary hemochromatosis, a condition linked to a gene (HFE) already present in SF v3.0. Both conditions are progressive infiltrative diseases that lead to end organ damage, including cardiomyopathy. However, while the most common pathogenic variants of hereditary hemochromatosis are present in individuals of European ancestry, the most common pathogenic variant of TTR occurs with a particularly high frequency in individuals of West African ancestry.

While case rarity and penetrance of disease-causing variants are factors that the pathogen working group takes into account when adding a gene or class of genetic variants to the list, the authors stated that the working group “identified that genes associated with conditions disproportionately affect one or would not be penalized.” A group that is least small if it is rare or has lower penetrance in the US population as a whole. In other words, we assess rarity and penetrance within the context of specific populations so as not to perpetuate or exacerbate the variances found in genomic medicine.”

Genes considered but excluded from ACMG SF v3.1

The paper also provides a background on three Cancer risk/Hematology genes that were considered but eventually excluded from the SF v3.1 update: RUNX1, RAD51C and RAD51D.

The working group voted not to include RUNX1 for three reasons cited in the paper, including limited data on penetrance and prevalence from genetically confirmed cohorts (as opposed to family or clinic).

RAD51C/D was previously reviewed for inclusion in the ACMG SF v3.0 List in connection with its association with ovarian cancer risk. As two recent studies on breast cancer were released, the working group has re-examined these genes in relation to breast cancer risk. The rationale for the deletion of RAD51C/D has been provided. The SFWG is already discussing other moderate penetrance breast cancer genes and has established criteria for ‘keeping a minimum list of genes For the recommended return” and “handle like cases alike”.

ACMG issues new recommendations for reporting secondary findings in genetic sequencing

more information:
David T. Miller et al, ACMG SF List v3.1 for Reporting Secondary Findings in Clinical Exome and Genome Sequencing: An American College of Medical Genetics and Genomics (ACMG) Policy Statement, Genetics in medicine (2022). DOI: 10.1016 / j.gim.2022.04.006

David T. Miller et al, Correction to: ACMG SF v3.0 List for Reporting Secondary Findings in Clinical Exome and Genome Sequencing: ACMG Policy Statement, Genetics in medicine (2021). DOI: 10.1038 / s41436-021-01278-8

Submitted by the American College of Medical Genetics and Genomics

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