Contributed Commentary by Madhuri R. Hegde
August 20, 2021 | For the benefit of laboratory and healthcare professionals, the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) published joint guidelines in 2015 aimed at standardizing terminology and the classification of sequence variants uncovered through genetic testing. Understandably, in the several years since then, there have been tremendous advances in this field of molecular diagnostics such as next-generation sequencing (NGS) technologies unlocking new opportunities to understand an individual’s unique genetic makeup. Armed with these insights, healthcare providers can personalize therapeutic options for their patients with genetic diseases, helping to manage or treat them altogether. More recently, NGS has allowed for SARS-CoV-2 surveillance and tracking the evolution of this virus and its growing number of variant strains. In the next several years, NGS could play an even greater role in infectious disease testing, human virome, microbiome and for detection of bacterial contamination in food and other matrices.
There is a growing body of research aimed at evaluating clinical response to therapies specifically targeted to suspected genetic diseases. In many cases those therapies rely on the accurate classifications of specific genetic variants, thereby delaying therapeutic intervention. For this reason, there is no better time than now to revisit the foundational framework set out by the ACMG and AMP in 2015 to account for new and emerging factors that play a critical role in understanding and treating genetic diseases to arrive at an improved variant classification schema.
Assembling the 2015 Guidelines
It would surprise few people to hear that we have a much greater understanding of the human genome today than we did just several years ago. While it once took years to sequence the human genome, NGS technologies have shortened this process to just a few days. And, as further context, prior to the creation of the 2015 ACMG/AMP guidelines, the scientific community had a fair understanding of ~200 of the ~22,000 genes in the human genome. Today, there are ~6,000 identified genes that have been shown to be causative of ~7,000 disorders.
This rapid escalation in our understanding of the human genome necessitated a common set of guidelines for researchers and clinicians to work from, particularly for determining the pathogenicity of variants. Prior to the 2015 guidelines, making these types of classifications relied on pulling information from disparate data sources, publications and other resources on inheritance patterns. For that reason, it took a committee of geneticists—myself included—two years to aggregate information, examine case examples and compile industry best practices that would help the community develop strategies for interpretations of genomic reports. These same genomic reports influence clinical decisions, interventions, or determine eligibility in certain clinical trials—further proving the need for ACMG/AMP guidelines to reflect the latest industry advances and discoveries in genetics and genomics.
Genetic Counseling in the Automation Age
Perhaps the most dramatic difference in clinical assays today is the technology used. The latest generation of NGS technologies enable the detection of inherited cancers and a great number of rare diseases like Duchenne muscular dystrophy, severe combined immunodeficiency (SCID), Tay-Sachs and Gaucher diseases, to name a few. In order to interpret data, genetic counselors are leveraging artificial intelligence and machine learning capabilities built into laboratory software programs. Harnessing these new capabilities reduces the complexity and rate of error inherently involved in sequencing and variant classification, however some level of human intervention will always be necessary in variant analysis.
Genetic counselors are now tasked with creating clinical reports using NGS technologies—oftentimes in collaboration with variant classification scientists—and ensuring that physicians accurately interpret these reports to create care plans for their patients. This becomes increasingly difficult when a report contains a variant of unknown significance (VUS), the nature and expression of which cannot be confirmed as either benign or pathogenic. This precise challenge points to an area of improvement for future iterations of the ACMG/AMP guidelines: accounting for in vivo physiological response to treatment in determining genomic variant pathogenicity.
A New Era in Precision Medicine
As professionals in the health and science field, we know that early detection and diagnosis lead to critical clinical interventions that prevent future health crises as successfully demonstrated by the newborn screening program. If those interventions are administered early on and are based on an individual’s unique genetic makeup, the more likely it is that they will be effective. This is why the effect of therapies specific and targeted to treatable genetic diseases must be considered as additional criteria to future updates of the joint ACMG/AMP guidelines—a proposal explored further in a paper recently published by Genetics in Medicine. These applications of “precision medicine” could have a significant impact in patient care, and if documented, could help others be cared for in the future.
Furthermore, precision medicine does not imply complexity. Many are interventions and therapeutic options available that could have a dramatic positive impact in the lives of people, such as nutritional replacement or medical foods. In other cases where there may be a greater level of certainty about a sequence variant (ideally based on more comprehensive genetic workup), gene therapies hold promise for improving an individual’s quality of life.
Vision for the Future
It is important to remember that we are still very much in the early days of genetics and genomic interpretation. There is always going to be room for improvement, and it is highly unlikely that we will ever have a single source of knowledge or guidance for all cases and applications of genomic testing.
As geneticists, clinicians and researchers, what we can do and continue striving for is ongoing collaboration and education of others in this field. By contributing to publicly accessible databases like ClinVar and adding to the growing body of research in the area of variant interpretation, patient care is certain to improve across the board.
Dr. Madhuri Hedge is the senior vice president and chief scientific officer at PerkinElmer Genomics. She is a medical geneticist, a board-certified diplomat in clinical molecular genetics by the American Board of Medical Genetics, and a fellow of the American College of Medical Genetics and Genomics. She received a B.Sc. and M.Sc. from the University of Bombay and a Ph.D. from the University of Auckland. She completed post-doctoral studies at Baylor College of Medicine. She can be reached at Madhuri.Hegde@PERKINELMER.COM.