NEW YORK (GenomeWeb) – The American College of Medical Genetics and Genomics has updated its list of genes that it recommends laboratories report secondary findings from when they perform clinical exome and genome sequencing tests.
In 2013, the ACMG recommended that clinical laboratories report back secondary findings from 56 genes, variants of which are known to cause severe disease but for which knowledge of the variants could lead to clinically relevant actions. It issued its recommendations as clinical exome and genome sequencing tests began to proliferate without any standards in place, and has since updated its policies, clarifying that patients should have the option of receiving such results and that the recommendations apply to both adults and children.
The ACMG also established a working group to curate and update the list periodically. In its latest update published today in Genetics in Medicine, ACMG has added four new genes to its list and removed one gene. In addition, it has sought to standardize the process by which it evaluates genes by including a semiquantitative metric for determining actionability, and outlined its future plans to consider pharmacogenomics variants.
As genomic sequencing becomes more widespread, it will have broad medical, legal, social, and economic implications, the authors wrote, and "it will be important for the genomics community to study the impact of [secondary findings] on the busy clinician, individual patients and families, and populations at large."
Additions to the list, which now consists of 59 genes, include BMPR1A and SMAD4, which are associated with juvenile polyposis; ATP7B, which is associated with Wilson disease; and OTC, which is associated with ornithine transcarbamylase deficiency. The working group removed MYLK, which is associated with familial thoracic aortic aneurysm and dissection.
The ACMG working group considered six genes that had been nominated between March 2015 and March 2016, including the four it added, the one it removed from the list, and an additional gene, PTCH1, related to basal cell carcinoma, that the group decided did not meet its criteria for impacting medical management.
The group also laid out a new process for curating and updating the list over time and for accepting and evaluating gene nominations. For its current gene list, the group accepted nominations only from ACMG members, but in the future, it plans to accept nominations from other professional organizations, including genetic counselors, primary care clinicians, and other clinical specialists.
In addition, it has developed a preliminary form for nominating PGx genes and variants and is working on developing a means by which to evaluate the genes and their clinical impact.
The Clinical Pharmacogenetics Implementation Consortium has already developed management recommendations based on PGx variants, but, according to the ACMG group, "assessing the impact of these results on clinical outcomes has proven difficult due to a lack of randomized controlled trials and small numbers of patients for whom results are available."
Reporting PGx variants from clinical exome and genome tests pose additional challenges, as well, the authors noted. Some PGx genes have pseudogenes and it can be difficult to distinguish variants in the pseudogene from the actual gene. Some PGx results are based on haplotypes made up of several variants, some of which are intronic and would not be covered by a clinical exome test. The authors also noted that the "star allele" nomenclature may need to be simplified, as it is not always familiar to geneticists. In addition, the authors noted that PGx results are not always needed at the time that a clinical exome test is ordered. However, they wrote that they plan to focus on PGx coding variants related to commonly prescribed drugs as well as those with serious adverse effects.