Approach to Genetic Evaluation for Advanced Paternal Age
Helga Toriello (Chair), Elena Ashkinadze, Yavuz Bayram, Robert Best, Yang Cao, Sau Wai Cheung, Priya Prasad, Aleksander Rajkovic PP&G Committee
We propose to revise the 2008 document into a "Points to Consider" format that will define terms used in this field, include updated information on the effects of advanced paternal age on reproductive risk, and discuss the possibility of advanced paternal age as a factor to consider when weighing options for assisted reproductive technologies and the monitoring of pregnancies. This document will be primarily targeted at clinicians and genetic counselors. Status: Document in development.
Consideration of inherited cancer risk on a continuum: An international and multidisciplinary perspective: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
Tuya Pal (Chair), Helen Hanson (Co-chair), Joseph Christopher, Will Foulkes, Paul James, Susan Klugman, Allison Kurian, Julie Mak, Alvaro Monteiro, Mark Robson, Douglas Stewart, Esteban Symonds, Marc Tischkowitz PP&G Committee
In the field of inherited cancer predisposition, the concept that risk of a specific cancer lies on a continuum (rather than based on a binary classification) of a germline pathogenic or likely pathogenic variant, is becoming increasingly important to consider. Historically, in the inherited cancer predisposition field, penetrance estimates have been anchored to genes based on ‘typical’ risks attributed through the literature. In addition, penetrance estimates have historically been ascertained “phenotype first,” meaning from families with a notable personal or family history bringing them to medical attention. Phenotypic ascertainment can inflate penetrance estimates. The ability to use the “genotype-first” approach (or genomic ascertainment) is a significant development in refining penetrance estimates. Using genes established to be associated with breast cancer as an example: from decades of primarily phenotypic ascertainment studies, BRCA1 and BRCA2 are considered to be ‘high penetrance genes’ imparting a lifetime risk of breast cancer generally in the range of 60-70%, while the ‘moderate penetrance’ CHEK2 and ATM genes are associated with a lifetime risk of breast cancer generally in the range of 20-30%. However, there are multiple factors that can impact risk. Status: Document in development.
Detection of repeat expansion variants using next generation sequencing: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
Saurav Guha (Co-chair), Honey Reddi (Co-chair), Shreshtha Garg, Akanchha Kesari, Indee-Shree Rajan-Babu, Nancy Rose, Bryce Seifert Lab QA Committee
Repeat expansion (RE) disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. At least 50 disorders associated with repeat expansion have been described to date. Accurate genotyping is critical to the molecular diagnosis of RE disorders as repeat length often influences disease severity and age of onset of clinical symptoms. Detection of repeat expansions is currently performed with PCR–based assays or with Southern blots for large expansions. Although highly sensitive in detecting and genotyping repeat expansion alleles, PCR and Southern blot tests have several limitations. They are time- and labor-intensive, require extensive optimization, and do not permit concurrent analyses of more than a handful of RE loci. Status: Document is in development.
Global Access to Genetic Resources: Concerns, Advances, and Future Directions
ELSI and COE Committees
Genetic disorders affect individuals throughout the world. Globally, the availability and accessibility of genetic testing and genetic information/resources are inconsistently and unequally distributed. Even in areas where genetic resources are available, certain populations may be less likely to get tested and may experience a lower diagnostic yield with testing. The combination of this and lack of access leads to inequitable health care throughout the world as certain populations are less often included in databases, clinical trials, and specific therapeutic advancements. As genetic testing continues to grow as part of standard of medical care, if global representation is not addressed, health disparities will be exacerbated. Topics discussed in this statement include: availability of genetic providers, testing, and information globally; genetic laboratory accessibility; populations included and those that are underrepresented in the uptake of genetic testing and in genetic databases; actions taken to address some of these issues and future directions. The goal of this Points to Consider is to bring attention to current pitfalls in global accessibility to genetic testing as well as to highlight some of the ongoing efforts to help reduce health disparities and provide equitable and culturally conscious care for all. Status: Proposal is in development.
Management of Hyperammonemia in Neonates Suspected of Having a Urea Cycle Disorder
Lindsay Burrage (Co-chair), Brett Graham (Co-chair), Nicholas Ah Mew, Margo Breilyn, Andrea Gropman, Steven Lang, Erin MacLeod, Shina Menon, Amarilis Sanchez-Valle, Amanda Sonntag, Monica Wojcik Therapeutics Committee
Neonatal hyperammonemia is a life-threatening complication of multiple inborn errors of metabolism, including the urea cycle disorders. With improved long-term therapies, such as nitrogen-scavenging agents and liver transplantation, the early recognition and initiation of therapy to rapidly reduce ammonia levels is critical for maximizing long-term outcomes in urea cycle disorders. In this Points to Consider, the workgroup seeks to address this overarching question: What are important factors to consider when managing a neonate with hyperammonemia? Status: Proposal is in development.
Perspectives on Off-Label Use of Therapeutics in Rare Diseases, Points to Consider
Mari Mori (Chair), Irene Chang, Dwight Koeberl, Jennifer Malin, Andres Morales Corado, Eva Morava Therapeutics Committee
FDA-approved specific therapy is not available to over 95% of rare diseases despite the success of the 1983 Orphan Drug Act (ODA) which provides fast-track FDA approval, marketing protection, tax incentives, and funding for clinical research in rare diseases. As a result, patients with rare genetic diseases often rely on off-label prescriptions, such as dextromethorphan for glycine encephalopathy. Insurance coverage of off-label prescriptions varies widely. Some insurers may agree to cover the off-label use based on a published compendium or published evidence. However, they may deny coverage even when the use aligns with clinical guidelines. Following a successful plenary session organized by the Therapeutics Committee in 2025, this points to consider document aims to outline the recurrent themes raised by both the speakers and audience through the event while providing potential solutions for addressing them, including collaborations from all parties involved (academics, industry, regulatory bodies, advocacy groups) to ensure equitable access regardless of an individual’s background or disease, and to call for a mechanism to provide guidelines for widely accepted off-label practices that insurance companies can adhere to. Status: Document in development.
Points to Consider for Inclusion of Genes Associated with Treatable Conditions in Newborn Sequencing Studies
Amanda Thomas-Wilson (Co-chair), Brett Graham (Co-chair), Wendy Chung, Laura Duque Lasio, Nina Gold, Mike Murray, Juanita Neira, Bradford Powell, Ross Ridsdale, Scott Ryall, Katie Sapp, Curt Scharfe, Marek Svoboda Therapeutics Committee
The utility of newborn sequencing studies are being demonstrated through several ongoing projects and collaborations worldwide. While most of these studies are undertaken using an in silico gene panel on a genome or exome platform, there is currently no guidance on gene selection for a newborn sequencing panel and they are lab or project specific. Concurrently the number of gene or disease specific therapies approved for germline genetic disorders is also rapidly increasing. While the American College of Medical Genetics and Genomics has issued guidance for reportable secondary findings for medically actionable adult conditions, no such guidance is currently available for pediatric conditions, specifically those with targeted therapies that when initiated pre- or peri-symptomatically may reduce morbidity and/or mortality. Status: Document in development.
Points to consider for reporting of variants in the prenatal setting
Elizabeth Spiteri (Chair), Saurav Guha (Co-chair), Vimla Aggarwal, Yassmine Akkari, Nina Gold, Nan Jiang, Leandra Tolusso Lab QA Committee
There is currently limited guidance on reporting of various types of variants on prenatal testing. The guidance that is available is often targeting a prenatal population that is referred for testing based on a pre-existing risk factor. As testing is offered to a broader population without additional risk factors reporting guidelines that are available may not be relevant. Status: Document in development.
Points to consider for the clinical validation and implementation of optical genome mapping (AMP, CAP, CGC to be involved)
Yassmine Akkari (Chair), Vimla Aggarwal (Co-chair), Caroline Astbury, Rashmi Kanagal-Shamanna, Sung-Hae (Sue) Kang, Brynn Levy, Gordana Raca, Honey Reddi, Nikhil Sahajpal, Jennifer Sanmann, Lina Shao Lab QA Committee
For an increasingly large number of constitutional and neoplastic disorders, the identification of specific numerical or structural abnormalities is often necessary for diagnosis, risk stratification and/or personalized treatment. Technological improvements coupled with the increasing need for laboratory automation and workflow optimization have fueled the interest in implementation of optical genome mapping (OGM) in clinical laboratories. OGM visualizes high molecular weight DNA allowing for an efficient evaluation of both structural and copy number aberrations of the genome in a single assay. While clinical care has traditionally relied on conventional cytogenetic studies, including G-band analysis, fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA), the emergence of OGM has allowed the detection of chromosomal aberrations, both balanced and unbalanced, in a single assay. However, due to its recent adoption into the clinical realm, there is a lack of standardization regarding validation and implementation of this technology in the clinical setting. Although several studies have been published on the clinical utility of this assay in various genomic diseases, there still exists considerable uncertainty on how to best utilize this technology in diagnostics. There is also a notable absence of standards or recommendations for clinical laboratories to validate and interpret OGM findings. Status: Document in development.
Points to Consider for the implementation of DNA methylation arrays for clinical diagnostics (AMP, CAP to be involved)
Nan Jiang (Chair), Honey Reddi (Co-chair), Leomar Ballester, Chetan Bettegowda, Jianling Ji, Marco Leung, Ditte Primdahl, Nancy Rose, Bekim Sadikovic, Lucas Santana dos Santos, Matija Snuderl, Matthew Tedder Lab QA Committee
DNA methylation is an epigenetic modification that plays an essential role in regulating gene expression, consequently exerting influence over a broad range of biological processes and diseases. For decades, methylation tests on specific gene loci or regions have been utilized primarily on the diagnosis of imprinting disorders or the detection of methylation-based cancer biomarkers. With the introduction of DNA methylation arrays, it has become feasible to quantitatively profile DNA methylation across the genome. This allows for the detection of a broader range of constitutional disorders and more precise classifications of various tumors. In recent years, DNA methylation arrays have been adopted and clinically validated for the diagnosis of both constitutional and neoplastic disorders which have aberrant DNA methylation patterns. However, there is a lack of standardization regarding validation and implementation of this technology in the clinical setting. Although several studies have been published on the clinical utility of this assay in various genomic diseases, there still exists considerable uncertainty on how to best utilize this technology in diagnostics. There is also a notable absence of standards or recommendations for clinical laboratories to interpret DNA methylation array findings. Status: Document in development.
Points to consider for the next-generation sequencing-based detection of copy number abnormalities (CNAs) and balanced chromosomal rearrangements in neoplastic disorders: A statement of the American College of Medical Genetics and Genomics (ACMG)
Yassmine Akkari (Chair), Linda Baughn (Co-chair), Cynthia Hawkins, Nan Jiang, Ross Levine, Trevor Pugh, Gordana Raca, Kathleen Schieffer, Soheil Shams Lab QA Committee
Technological improvements coupled with large cohort studies have fueled unprecedented advances in our understanding of cancer genomes. For an increasingly large number of neoplastic disorders, the identification of specific mutations, copy number abnormalities (CNAs) or chromosomal rearrangements is often necessary for diagnosis, risk stratification and/or personalized treatment. Presently, a shift in the modality through which chromosomal rearrangements and CNAs are detected and reported has emerged. While clinical care has traditionally relied on cytogenetic studies, including karyotyping, fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA), next generation sequencing (NGS) data is facilitating similar analyses. However, there exists considerable variability in the design, coverage and analytical pipelines that inform NGS-driven approaches for detection of these abnormalities. Moreover, there is also a notable absence of standards or recommendations for clinical laboratories to design, validate and interpret these findings. Acquired CNAs can vary widely both in size (from small intragenic deletions and duplication to whole genome doubling events) and in copy number states (from homozygous deletions to focal, high-level amplifications); it is not uncommon that patterns of concurrent CNAs rather than individual aberrations have diagnostic or prognostic significance. Status: Document in development.
Points to consider for workplace genomic testing
Kunal Sanghavi (Co-chair), Marc Williams (Co-chair), Maria Frangenberg, Michelle McClure, Anya Prince, Laurie Seaver, Matteo Vatta, Ellen Wright Clayton ELSI Committee
More than 157 million people in the US receive their healthcare insurance through employer healthplans. In some cases, employers are offering voluntary workplace genomic testing (wGT) through such health plans. Stakeholders Assessing Genetics with Employers (SAGE), a federally funded research project focused on assessing “non-indication based genetic testing” (NIBGT) provided frameworks fordemonstrating the value of NIBGT (that includes wGT) and for considering future research investments. A recent study providing an overview of vendors offering wGT reported that 53% (8/15) of vendors provided professional health or genetic consultations and only 4 vendors tested for pathogenic variants. While existing studies provide guidance for employers, our timely proposed project will inform policy makers who review the safeguards to protect privacy and confidentiality of employees, data security, and wellness programs. Status: Document in development.
Points to Consider in the Genetic Evaluation of Living Kidney Donors
Christie Thomas (Co-chair), Mir Reza Bekheirnia (Co-chair), Deborah Adey, Margaret Freese, Ana Iltis, Malek Kamoun, Lakshmi Mehta, Jeffrey Pannekoek, BeLinda Pressley, Stuart Scott, Xiangling Wang PP&G Committee
People who volunteer to donate a kidney undergo rigorous medical and psychosocial evaluation before being accepted to be living kidney donors (LKD). Part of the goal of the evaluation is to verify that the LKD is currently in good health and does not have any kidney disease nor any indication of excessive future risk of kidney disease. With the availability of several genetic testing modalities, it is now possible to screen asymptomatic LKD candidates for genetic variants to better predict future risk of kidney disease. DNA-based screening of LKD candidates can identify individuals destined to develop dominant or recessive Mendelian disease with later age of onset (e.g., ADPKD) and individuals with genetic variants that may independently (e.g., APOL1) or collectively (polygenic risk) increase susceptibility for future kidney disease. The delivery of DNA-based screening in LKD evaluation typically employs a non-traditional genetic health-care model where genetic counseling, genetic testing and dissemination of test results is managed by nephrologists and transplant center specialists without easy access to genetics professionals (e.g., genetic counselors and clinical geneticists). Status: Document in development.
Points to consider in the preparation for acceleration of emergence of new therapeutics: A statement of the American College of Medical Genetics and Genomics (ACMG)
Andres Morales Corado (Co-chair), Brett Graham (Co-chair), Holly Bernal, Lindsay Burrage, Ed Esplin, Jaya Ganesh, Hyunyong (Howard) Koh, Julianne O’Daniel, Hilary Vernon, Jerry Vockley Therapeutics Committee
The field of medical genetics is facing new challenges as the result of the increasing number of FDA-approved therapies for rare genetic disorders. Accordingly, this Points to Consider document aims to outline some of these new challenges with potential solutions for addressing them. In this document, we will address the need for educational resources to train genetics residents, medical geneticists and other providers about these new therapies, the adaptations needed in our clinics to meet the needs for administration of these therapies including multi-disciplinary collaborations with other provider types, and the mechanisms necessary to ensure equitable access to these new therapies for all patients regardless of geography and socioeconomic status. Status: Document in development.
Points to consider in the reporting of variants of uncertain significance in genetic and genomic testing: A statement of the American College of Medical Genetics and Genomics (ACMG)
Heidi Rehm (Co-chair), Lora Bean (Co-chair), Aya Abu-El-Haija, Vimla Aggarwal, Yassmine Akkari, Caroline Astbury, Farid Barquet Ramos, Hunter Best, Laura Conlin, Steven Harrison, Nan Jiang, Paul Kruszka, Dianalee McKnight, Chloe Mighton, Tiffany Nguyen Dolphin, Christie Thomas Lab QA Committee
Over 30% of genetic testing reports contain a variant of uncertain significance yet physicians and patients are often ill-prepared to manage VUSs and insurers are concerned about downstream costs. Genetic testing is increasingly deployed in non-diagnostic contexts such as family history or preventive purposes with low prior probability in which case the reporting of VUS may, on balance, create more harm than good. The ACMG/AMP/CAP/ClinGen SVC v4.0 standard for sequence variant classification will soon be released and provide an easy framework for subdividing VUS by likelihood of pathogenicity. This points to consider document will provide considerations for laboratory policies in reporting of VUSs. It will cover aspects related to: clinical indication; physician and patient preferences for receiving VUSs on reports; use of the new VUS sub-tiers in reporting; use of report format strategies to influence the attention paid to VUSs. Status: Document in development.
Points to consider on the impact of 21st Century Cures Act on genomic medicine: A statement of the American College of Medical Genetics and Genomics (ACMG)
Sara Rabin-Havt (Co-chair), Samuel Huang (Co-chair), Perry Chan, Bimal Chaudhari, Tanya Eble, Barbara Evans, Stephanie Fullerton, Jesse Hunter, Kathleen Pope ELSI Committee
Pre- and post-testing counseling including results disclosure planning has long been a crucial tenet of genetic consultation. The new Office of the National Coordinator for Health Information Technology (ONC) Cures Act Final Rule, which includes provisions against information blocking, is likely to significantly impact current results disclosure practice norms. Information blocking is defined as a practice by an actor (including a healthcare provider) that is likely to interfere with access, exchange or use of health information. While this is intended to benefit patients and empower them with access to their own health information, a concerning consequence is a risk of bypassing disclosure by the healthcare team. While this risk is not unique to genetics, it does require that genetics providers consider the timing and approach to results disclosure. Even though the ONC has provided additional guidance on prohibition of information blocking and carved out 8 exceptions, the real-world implementation and intersection with clinical genomics practice remains unclear and warrants further investigation and guidance. Status: Document in development.
Points to Consider statement regarding resources needed to administer gene therapy
Dwight Koeberl (Co-chair), Julie Porter (Co-chair), Elizabeth Baker, Bronwyn Bateman, Natario Couser, Ed Esplin, Jaya Ganesh, Brett Graham, Steven Gray, Nicola Longo, Loren Peña, Jerry Vockley Therapeutics Committee
The question to be addressed by this Points to Consider Statement is “what resources are needed to participate in gene therapy clinical trials and deliver it in clinical practice?”. The output will be a “Checklist of Gene Therapy Infrastructure” that will be relevant to facilities that are responsible for gene therapy product acquisition, storage and administration. The need for this Statement is urgent, since gene therapy is a novel and expanding modality of treatment that has unique requirements for delivery that differ from previous therapies such as small molecule drugs or enzyme replacement therapies. Furthermore, medical geneticists are already involved in the development and delivery of gene therapy, and should make recommendations regarding the needs for infrastructure to support it. This project represents follow-up to an expert panel convened by the National Organization for Rare Disorders (NORD) to address topics related to rare disorder therapies. Status: Document in development.
Pre-transplant genetic testing in potential bone marrow transplant (BMT) donors: A points to consider statement from the American College of Medical Genetics and Genomics
Bryce Seifert (Chair), Lyndsey Runaas (Co-chair), Matthew Avenarius, Sarah Bannon, Yulong Fu, Nan Jiang, Ender Karaca, Sarah Rapisardo Long, Honey Reddi, Nancy Rose, Christie Thomas Lab QA Committee
For individuals with genetic disorders undergoing bone marrow transplant (BMT), siblings or close relatives are often used as donors. In the pre-transplant setting, clinicians must often choose between targeted genetic testing on the donor for the diagnostic variant(s) specific to the recipient versus more extensive genetic testing on the donor (e.g., cytogenetic testing, NGS panel, exome, or genome sequencing). This decision can be influenced by many factors. This points to consider statement will discuss the type of testing utilized in pre-transplantation settings (e.g., cytogenetic testing, single variant analysis, targeted NGS panel testing, exome/genome sequencing), genes focused on in testing potential donors (secondary findings genes and/or genes that may impact transplant success in the recipient), and whether gene content varies based on the age of potential donors (minors versus adults). Discussing these factors through a points to consider statement will better equip clinicians and clinical laboratorians in determining the optimal approach to genetic testing in potential BMT donors in the pre-transplant setting, thereby supporting the best possible BMT outcome in the recipient. Status: Document in development.
Primer on privacy of genetic information: A points to consider statement for policymakers
Tina Hambuch-Hawks (Chair), Bob Best, Sheila Dobin, Lynn Fleisher, Marco Leung, Michelle McClure, Matt Might, Brandon Shaw, Ellen Wright Clayton AGA Committee
Privacy of genetic information is attracting a lot of attention from policymakers, including those in the US Congress. However, there seems to be little awareness regarding what genetic information is, how it is shared in clinical and research settings, and the many existing protections (such as those offered under the Common Rule and others). As a result, policies may be proposed that would have devastating unintended consequences on sharing of information for the purpose of clinical investigations or advancing medical research. For example, legislation has recently been progressing in multiple states that would override existing federal policies and require explicit consent for any use of genetic information and retention of specimens that contain genetic material regardless of deidentification. The tensions between individual control and data/sample sharing are confounded by some attributes of genetic samples and data. Further, regulations and guidelines already exist that provide conflicting information relating to the access, ownership, and use of generated genetic data. For example, there are several components of genetic data that, once generated, cannot or should not be deleted completely such as deidentified and classified variant information. Status: Document in development.
SCADD is Not a Disease
Amy Calhoun (Co-chair), Chanika Phornphutkul (Co-chair), Adviye Ayper Tolun, Gabrielle (Elle) Geddes, Stephanie Hacker, Emily Lisi, Alexandra Salser, Amarilis Sanchez-Valle, Wendy Smith, Elaine Spector PP&G Committee
Newborn screening for Short-chain acyl CoA dehydrogenase (SCAD) deficiency began in the late 1990s, and SCAD deficiency was added to the Recommended Uniform Screening Panel in 2005. SCAD deficiency was originally considered a very rare, serious disorder. However, once screening became widespread, clinicians found that prospectively ascertained individuals remained asymptomatic. Cascade testing leads to diagnosis of clinically well adults “affected” by SCAD deficiency. Currently, the majority of biochemical geneticists worldwide consider SCAD deficiency a biochemical phenotype and not a disease. Status: Document in development.
ACMG population screening: List of primary findings for reporting V1.0
Michael Murray (Co-chair), Sonja Rasmussen (Co-chair), Noura Abul-Husn, Ned Calonge, Marina DiStefano, Debra Duquette, Faith Fletcher, Muin Khoury, Bruce Korf, Murugu Manickam, Dena Matalon, Katherine Nathanson, Cynthia Powell, Maren Scheuner, Nadav Weinstock, Marc Williams ACMG Board of Directors
This proposed policy statement will use the evidence-based and criteria-driven approach described in the workgroup’s position statement to identify a minimal list of genomic variants to be prioritized by those institutions and organizations seeking to launch DNA-based population public health screening programs. It is proposed that this list be submitted for publication in GIM as version one (V1.0) of ACMG recommendations for specific genes and variants that should be assessed in order to deliver primary findings (PF) back to individuals with identified risk in population public health screening programs. Status: Document in development
Use of sex and gender identifiers in clinical and laboratory genetics and genomics: A policy statement of the American College of Medical Genetics and Genomics (ACMG) (AMP, CAP to be involved)
Mahmoud Aarabi (Co-chair), Fabiola Quintero-Rivera (Co-chair), Andrea Cantor, Natario Couser, Anna Essendrup, Margo Gallegos, George Khushf, Susan Klugman, Dena Matalon, Aleksandar Rajkovic, Eric Vilain, Svetlana Yatsenko, Kimberly Zayhowski COE and ELSI Committees
Sex and gender identifiers are integral to providing patient-centered and equitable healthcare. By recognizing and respecting the differences and needs related to sex and gender, healthcare providers can deliver more effective, culturally competent, and inclusive medical care. While sex and gender are distinct, they are interconnected factors that play a significant role in determining an individual's health and healthcare needs. In genetics and genomics, it is essential to recognize the complexity of sex and gender, understand the genetic factors associated with both, and approach patient care, testing and research participation in an inclusive and respectful manner. Status: Document in development.
DNA-based population screening: Approach to gene and variant selection
Sonja Rasmussen (Co-chair), Michael Murray (Co-chair), Noura Abul-Husn, Ned Calonge, Marina DiStefano, Debra Duquette, Faith Fletcher, Muin Khoury, Bruce Korf, Murugu Manickam, Dena Matalon, Katherine Nathanson, Cynthia Powell, Maren Scheuner, Nadav Weinstock, Marc Williams ACMG Board of Directors
DNA-based approaches to population health screening have the potential to significantly improve the early detection and prevention of cancers, heart disease, and other conditions associated with identifiable genomic risk. However, a broadly applicable evidence-based approach to the selection of genes and variants for prioritization in population screening does not currently exist. Status: Document in development.
Laboratory guideline for Turner syndrome “Update”
Vimla Aggarwal (Co-chair), Yassmine Akkari (Co-chair), Nan Jiang, Lauren Mohnach, Joie Olayiwola, Jennifer Sanmann, Teresa Smolarek, Daynna Wolff
Turner syndrome is a disorder of sex development with distinct clinical features and cytogenetic findings. In 2010, the ACMG Lab QA published a laboratory guideline for Turner syndrome (PMID: 20081420). These guidelines were re-affirmed in 2014. Although many guidelines have been published on the clinical management of this disorder, the ACMG publication remains, to date, one of the few guidelines on the cytogenetic workup of Turner syndrome. Herein, we propose an update of the 2010 guidelines and present new information regarding the diagnostic workup of this syndrome whenever applicable. Status: Proposal is being finalized.
Interpreting sequence variants: A joint consensus statement of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology “Update”
Les Biesecker (Co-chair), Steven Harrison (Co-chair), Ahmad Abou-Tayoun, Jonathan Berg, David Bick, Alicia Byrne, Elizabeth Chao, Sian Ellard, Julie Gastier-Foster, Izabella Karbassi, Heather McLaughlin, Ann Moyer, Anne O'Donnell-Luria, Sharon Plon, Heidi Rehm, Sue Richards, Lisa Vincent, Nicky Whiffin
Revision of ACMG Interpreting Sequence Variation Guideline: Revise current guideline to address ambiguities in some criteria as well as appropriateness and strength of other criteria; Develop mechanism for ongoing guideline addenda and to include gene-specific modifications from ClinGen Expert Panels as approved by the ClinGen SVI; Include recommendation on which variants are appropriate for use in varying clinical intended uses (e.g., diagnostic testing vs. screening otherwise healthy individuals); Consider establishing quantitative parameters for criteria; Accept updates from ClinGen SVI every 6 months to plan for and develop additional addenda. Status: Document in development.
Diagnosis and Management of Pompe Disease
Priya Kishnani (Co-chair), Judith Hobert (Co-chair), Ayesha Ahmad, Ankit Desai, Laura Duque Lasio, Amanda Joost, Amanda Thomas-Wilson, Rory Tinker
We propose to revise the 2006 Pompe Disease Diagnosis and Management Guideline, which remains a foundational resource but predates the FDA approval of enzyme replacement therapy (ERT), the widespread implementation of newborn screening and next-generation sequencing. This revision is necessary to address the critical gap in current guidance, particularly with respect to therapeutic advances and evolving management strategies. The original 2006 guidance document contains no discussion of ERT, providing a clean foundation upon which to build a modernized treatment section without conflicting legacy recommendations. Existing sections of the original 2006 guidance that remain relevant and applicable to today’s practice will be carried forward into the revised document, with newer supporting evidence added to the reference list. Status: Proposal is in development.
Genetic Counseling and Testing for Alzheimer Disease: A Practice Resource of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC)
Status: Proposal is in development.
Genetic Evaluation of Cardiomyopathy (HFSA to be involved)
Anwar Chahal (Co-chair), Kim McBride (Co-chair), Babken Asatryan, Mythily Ganapathi, Andrew Landstrom, Ana Morales, Nosheen Reza, Matthew Taylor, Anjali Tiku Owens, Matteo Vatta, Stephanie Ware
We propose to revise the 2018 document titled ‘Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)’ as there have been marked advances over the last 6 years in the field of Mendelian cardiomyopathies with causal genes and advanced FDA-approved precision therapies, as well as phase II and III gene therapy trials. This revision will outline best practices targeted at medical geneticists, genetic counselors, and other clinicians. Status: Document in development.
Genetic Evaluation of Monogenic Chronic Kidney Disease
Christie Thomas (Co-chair), Xiangling Wang (Co-chair), Margaret Freese, Balram Gangaram, Yuan Ji, Amar Majmundar, Sarah Mazzola, Lakshmi Mehta, Ann Moyer, Tam Sneddon, André Weinstock, Matthias Wolf
Monogenic kidney disease is reported in approximately 10% of a random sample of older adults on dialysis but in nearly 40% of persons suspected of genetic kidney disease. Genetic kidney disease is often unrecognized especially when it presents at an older age, occurs in the absence of a family history, or has a renal-limited presentation. Identification of the genetic basis of kidney disease has several potential advantages including clarification of the diagnosis and prognosis, anticipation of extrarenal presentations, directing genetic variant-guided therapy and in the case of kidney transplant recipients, optimizing perioperative management, predicting disease recurrence, and permitting the evaluation of related living donors and other asymptomatic family members. Status: Document in development.
Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
Helen Hanson (Co-chair), Joanne Ngeow (Co-chair), Douglas Stewart (Co-chair), Esteban Astiazaran Symonds, Judith Balmaña, Ilana Cass, Jianbang Chiang, William Foulkes, Paul James, Arielle Katcher, Susan Klugman, Felix Kommoss, Alicia Livinski, Julie Mak, Tuya Pal, Marc Tischkowitz, Nicoleta Voian, Myra Wick
BRIP1, RAD51C and RAD51D, are considered as moderate penetrance ovarian cancer predisposition genes. Whilst risk reducing bilateral salpingo—oophorectomy is considered standard of care for high risk ovarian cancer risk genes, recommendations for BRIP1, RAD51C and RAD51D are more nuanced as risk is largely conferred after age 50 and therefore the risk-benefit of an early surgical menopause needs to be carefully balanced with age specific and lifetime risks. It is therefore important to develop consensus and a framework for cancer risk management strategies based on cancer risks in conjunction with age distribution and other potential modifying factors such as family history. Furthermore, there has historically been conflicting data on the association of these genes with breast cancer risk, but recent large case control studies have provided more robust evidence that RAD51C and RAD51D are associated with breast cancer predisposition, whilst BRIP1 is not. Status: Document in development.
The Therapeutic Importance of Germline Testing in Oncology Patients
Ed Esplin (Chair), Paldeep Atwal, Demitri Dedousis, Heather Dorsey, Harry Layton Lesmana, Huma Rana, Scott Ryall, Maren Scheuner, Vivek Subbiah
The therapeutic implications of germline testing for a variety of cancer indications has grown rapidly in recent years, with continued advancements in improving patient care and outcomes anticipated. Despite germline genetics-based FDA-approved therapies and clinical treatment trials, a small fraction of patients for whom genetic testing is recommended receive it. This may, in part, be due to a lack of awareness among clinicians and patients of the current guidelines surrounding germline testing in the oncology space. Furthermore, the clinical impact of this testing, including identifying patients requiring precision therapy, enrolling in cutting-edge clinical trials, establishing secondary cancer prevention through surveillance and risk-reducing intervention, and promoting cascade family genetic testing are unrealized. Status: Proposal is being finalized.
Prenatal cell-free DNA (cfDNA) screening: A technical standard of the American College of Medical Genetics and Genomics (ACMG) and the College of American Pathologists (CAP)
Shashirekha Shetty (Co-chair), Ross Rowsey (Co-chair), Sucheta Bhatt, Phillip Cacheris, Benjamin Hilton, Sung-Hae (Sue) Kang, Edward Kloza, Brynn Levy, Bryce Seifert, Erin Wakeling
Historically, prenatal screening for common chromosomal aneuploidies involved maternal age assessment, measurements of maternal serum analytes and/or ultrasonography. Advances in genomic technologies, such as next generation sequencing, led to prenatal cell-free DNA screening of placenta-derived cell-free DNA present in the maternal blood to identify fetuses at increased risk of Trisomy 13, 18 and 21 and aneuploidy of sex chromosomes. Since its introduction in 2009, prenatal cell-free DNA screening has achieved rapid clinical acceptance and is currently the most sensitive and specific screening test for the common chromosomal aneuploidies. Status: Document in development.
Section E9 of the ACMG Technical Laboratory Standards for fluorescence in situ hybridization (FISH)
Sung-Hae (Sue) Kang (Co-chair), Karen Tsuchiya (Co-chair), Yassmine Akkari, Julia Bridge, Andrew McFaddin, Lucilla Pizzo, Jennifer Sanmann, Lina Shao
This document represents a proposed update of Section E9 of the ACMG technical standards and guidelines: Fluorescence in situ hybridization (FISH), which was originally published in 2011 and reaffirmed in 2018. In October 2021, the Cytogenetics Lab QA subcommittee convened and agreed on updating this document to reflect current practices, and address challenges in validations and in the establishment of reference ranges. The project will be in collaboration with the CAP Cytogenetics Committee. Status: Document in development.
Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) “Update” (AMP, CAP to be involved)
Erin Rooney Riggs (Co-chair), Erik Thorland (Co-chair), Erica Anderson, John Herriges, Anne Higgins, Sung-Hae (Sue) Kang, Christa Lese Martin, Chelsea Lowther, Brynn Levy, Ludmila Matyakhina, Dominic McMullen, Daniel Pineda Alvarez, Lina Shao, Shashirekha Shetty, Andrea Vaags
The goal of this project is to update and revise the 2020 ACMG/ClinGen technical standards for interpretation and reporting of constitutional copy number variants (CNVs). Status: Document in development.
Technical standard for mucopolysaccharidoses metabolite testing
Anna Scott (Chair), Maria Descartes, Patricia Dickson, Marzia Pasquali, Dawn Peck, Sarah Young, Chelsea Zimmerman
Newborn screening programs are expanding to include lysosomal storage disorders (LSDs), raising awareness for these diseases and increasing demand for follow-up diagnostic testing. The availability of new therapies also requires accurate monitoring of disease status through analysis of specific biomarkers. The mucopolysaccharidoses (MPS) are a subset of LSDs that are characterized by accumulation of glycosaminoglycans (GAGs). New methodologies for analyzing GAGs and related analytes, especially those utilizing liquid chromatography-mass spectrometry (LC-MS/MS), are becoming increasingly widespread for the diagnosis and monitoring of patients with these disorders. However, different methods are used and there is no standardization regarding the use of internal standards, calibration material, and quality controls. This standard will focus on GAG testing and is intended to provide guidance on a standardized approach to test validation, independently from the method used. The document will educate clinicians and laboratorians about testing options with an emphasis on assay limitations and benefits. This standard will complement a document that is in progress describing lysosomal enzyme testing. Status: Document in development.
Cytogenetics defined: A technology-agnostic science for the detection of chromosomal aberrations in disease
Jennifer Sanmann (Chair), Vimla Aggarwal, Yassmine Akkari, Nan Jiang, Sung-Hae (Sue) Kang, Joie Olayiwola, Gordana Raca, Lina Shao, Elizabeth Spiteri
A significant number of constitutional and neoplastic disorders benefit from the identification of specific numerical and/or structural chromosomal abnormalities for appropriate diagnosis, risk stratification, and/or targeted therapy. As a result, the utilization of genetic testing that can provide this type of information is on the rise across the medical community, with ordering providers ranging from general practitioners to highly specialized genetics professionals. Simultaneously, the tools and technologies used to generate this clinically-relevant genetic information are evolving at a rapid pace. Examples of emerging technologies that provide insight into copy number and structural chromosomal aberrations include optical genome mapping and genome sequencing. Status: Proposal is being finalized.
Technical standards for the reporting and sharing of interpreted genomic variation: Guidance for journals and authors from ACMG, AMP, ASHG, CAP, CCMG, and HUGO
Hunter Best (Chair), Matt Avenarius, Lora Bean, George Burghel, Sara Cullinan, Laura Conlin, Isabelle De Bie, Fei Dong, Peter Freeman, Jordan Lerner-Ellis, Marco Leung, Jennifer Posey, Heidi Rehm, Somak Roy, James Solomon, Elizabeth Spiteri, Robert Steiner, Rachel Taylor
Variation in the sequence of the human genome is the basis of heritable (germline) disorders or may lead to a predisposition to non-heritable (somatic) disorders such as cancer. Proper documentation of sequence variation is critical in aiding in the clinical care of patients and also in the performance research studies. As such, accuracy in the description of reported sequence variants is of the utmost importance. Although HGVS nomenclature guidelines are widely accepted in the field of genetics, many journals do not adhere to these guidelines resulting in discrepant naming of identified/reported variants. This can directly impact clinical variant interpretation and therefore patient diagnosis/management. A technical standards document aimed at standardizing reporting variants across all major publishers would help to ensure that identified variants are correctly cataloged in variant databases. In turn this will help clinical laboratorians to accurately interpret rare variants identified in clinical genomic sequencing. Status: Document in development.
Arimoclomol and levacetylleucine for treatment of neurologic manifestations of Niemann-Pick disease type C: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)
Irene Chang, Bryce Mendelsohn, Jorge Rodriguez-Gil, Wendy Smith
This document will contain a brief update on two newly FDA-approved treatments for Niemann-Pick type C disease, arimoclomol and levacetylleucine. These are oral therapies approved to treat older children and adults. Status: Document is in development.
Chenodiol
Petros Giannikopoulos, Chung Lee, Andres Morales Corado, Marek Svoboda, Khoon Ghee Quennie Tan
This document is a brief therapeutics update on the newly FDA-approved drug, chenodiol indicated for the treatment of adult patients with cerebrotendinous xanthomatosis. Status: Document is in development.
Diazoxide choline in hyperphagia
Allyson Derry, Andrea Gropman, Nadia Merchant, Juanita Neira
This document is a brief therapeutics update on the newly FDA-approved drug, diazoxide choline extended release indicated for the treatment of hyperphagia in Prader-Willi Syndrome. Status: Proposal is in development.
Eladocagene exuparvovec-tneq
Sarah Elsea, Andres Morales Corado, Julie Porter, Kuntal Sen
This document is a brief therapeutics update on the newly FDA-approved drug, Eladocagene exuparvovec-tneq indicated for the treatment of adult and pediatric patients with aromatic L-amino acid decarboxylase deficiency. This is an adeno-associated virus vector-based gene therapy, administered through a one-time surgical session via four intraputaminal infusions. Status: Document is in development.
Mavorixafor
Mark Dulchavsky, Mark Hannibal, Harry Lesmana, Xiao Peng
This document is a brief therapeutics update on the newly FDA-approved drug, Mavorixafor indicated for the treatment of individuals 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis). In WHIM syndrome, CXC chemokine receptor 4 (CXCR4) pathogenic variants cause hyperactive CXCR4 signaling leading to retention of leukocytes in the bone marrow. This is an oral CXCR4 antagonist given on daily basis to increase the number of circulating mature neutrophils and lymphocytes. Status: Proposal is in development.