ACMG Statements and Guidelines
These online statements and guidelines are definitive and may be cited using the digital object identifier (DOI). These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical genetics services; they should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. Please refer to the leading disclaimer in each document for more information.
The clinical application of polygenic risk scores: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
Polygenic inheritance is a non-Mendelian form of inheritance in which the risk of a trait, disorder, or disease results from the combined contribution of variants from multiple genes. Most chronic illnesses and complex disorders are multifactorial and are associated with polygenic inheritance and environmental influences. Genome-wide association studies (GWAS) evaluate the association of specific loci with various complex disorders, such as cardiovascular disease, diabetes, cancer, neuropsychiatric conditions, or individual traits, such as height and blood pressure.The designated record set for clinical genetic and genomic testing: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
Individuals have a right to access certain information in their medical records as established under the Health Insurance Portability and Accountability Act of 1996 (HIPAA).1 The specific information to which individuals have access is called a designated record set (DRS), a legal term of art defined in the HIPAA Standards for Privacy of Individually Identifiable Health Information (Privacy Rule).2 The Privacy Rule is a federal medical privacy law that applies to most clinical laboratories operating in the United States.Solid organ transplantation in methylmalonic acidemia and propionic acidemia: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
Methylmalonic acidemia (MMA; OMIM 251000 , OMIM 251100 , OMIM 251110 , OMIM 277410 , OMIM 277400 ) and propionic acidemia (PA; OMIM 606054 ) are inborn errors of metabolism of the propionate pathway characterized by accumulation of methylmalonic acid and propionic acid, respectively, leading to acute presentations related to metabolic acidosis and hyperammonemia, as well as chronic heterogenous complications.Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)
This workgroup aimed to develop an evidence-based clinical practice guideline for the use of noninvasive prenatal screening (NIPS) for pregnant individuals at general risk for fetal trisomy 21, trisomy 18, or trisomy 13 and to evaluate the utility of NIPS for other chromosomal disorders.Considerations for policymakers for improving health care through telegenetics: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
Telegenetics, a form of telemedicine, is 2-way, interactive real-time electronic information communication between a patient and genetics health care professional(s) (ie, medical geneticists [physicians who specialize in genetics] and genetic counselors [health care workers with training in medical genetics and counseling]) as an alternate to providing health care in person at a medical office.1,2 These services include, but are not limited to, assessment, diagnosis, consultation, test result release, education, counseling, management of care, and/or aided self-management.ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)
The American College of Medical Genetics and Genomics (ACMG) previously published guidance for reporting secondary findings (SF) in the context of clinical exome and genome sequencing in 2013, 2017, and 2021.1-3 The ACMG Secondary Findings Working Group (SFWG) and Board of Directors (BOD) have agreed that the list of recommended genes should now be updated annually, but with an ongoing goal of maintaining this as a minimum list. Reporting of SF should be considered neither a replacement for indication-based diagnostic clinical genetic testing nor a form of population screening.Systematic evidence-based review: The application of noninvasive prenatal screening using cell-free DNA in general-risk pregnancies
Noninvasive prenatal screening (NIPS) using cell-free DNA has been assimilated into prenatal care. Prior studies examined clinical validity and technical performance in high-risk populations. This systematic evidence review evaluates NIPS performance in a general-risk population.Clinical evaluation and etiologic diagnosis of hearing loss: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals.Response to Righetti et al
We thank Righetti et al1 for their interest in our article titled Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG).2 We were pleased to learn that the investigators from the Australian Reproductive Genetic Carrier Screening Project (ARGCSP) are in agreement with many aspects of this practice resource.Clinical pharmacogenomic testing and reporting: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Pharmacogenomic testing interrogates germline sequence variants implicated in interindividual drug response variability to infer a drug response phenotype and to guide medication management for certain drugs. Specifically, discrete aspects of pharmacokinetics, such as drug metabolism, and pharmacodynamics, as well as drug sensitivity, can be predicted by genes that code for proteins involved in these pathways. Pharmacogenomics is unique and differs from inherited disease genetics because the drug response phenotype can be drug-dependent and is often unrecognized until an unexpected drug reaction occurs or a patient fails to respond to a medication.Measurement of lysosomal enzyme activities: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Assays that measure lysosomal enzyme activity are important tools for the screening and diagnosis of lysosomal storage disorders (LSDs). They are often ordered in combination with urine oligosaccharide and glycosaminoglycan analysis, additional biomarker assays, and/or DNA sequencing when an LSD is suspected. Enzyme testing in whole blood/leukocytes, serum/plasma, cultured fibroblasts, or dried blood spots demonstrating deficient enzyme activity remains a key component of LSD diagnosis and is often prompted by characteristic clinical findings, abnormal newborn screening, abnormal biochemical findings (eg, elevated glycosaminoglycans), or molecular results indicating pathogenic variants or variants of uncertain significance in a gene associated with an LSD.Stewardship of patient genomic data: A policy statement of the American College of Medical Genetics and Genomics (ACMG)
Human genomic data linked to health records have become valuable in the quest to establish correlations between disease and genetic information. As a result, it has become increasingly common for patient genetic information obtained through clinical testing or other means to be de-identified and linked to health records for sale or transfer to a third party for research and development purposes (eg, novel drug targets, patient and provider tools for managing health care). Unlike many other elements within the de-identified data set, however, the patient’s genetic information in various forms (eg, DNA sequence, RNA sequence, aggregated variant data, optical mapping) may be sufficiently information-rich to permit reidentification of the patient using informatics tools in some cases and is considered by some to be inherently identifiable.Points to consider to avoid unfair discrimination and the misuse of genetic information: A statement of the American College of Medical Genetics and Genomics (ACMG)
In this era of precision medicine, the incorporation of genetic and genomic information, herein referred to as genetic information, into health care has gained unprecedented attention. As a result of the rapid decline in the cost of DNA sequencing, these data are now routinely used for diagnostic purposes and preventive health screening. In addition to the application of genetic information to support diagnosis and management, consumers may directly access various genetic testing–based products for medical and nonmedical uses, and some employers now offer wellness genetic testing to their employees as a benefit.Interpretation and reporting of large regions of homozygosity and suspected consanguinity/uniparental disomy, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Genomic testing, including single-nucleotide variation (formerly single-nucleotide polymorphism)–based chromosomal microarray and exome and genome sequencing, can detect long regions of homozygosity (ROH) within the genome. Genomic testing can also detect possible uniparental disomy (UPD). Platforms that can detect ROH and possible UPD have matured since the initial American College of Medical Genetics and Genomics (ACMG) standard was published in 2013, and the detection of ROH and UPD by these platforms has shown utility in diagnosis of patients with genetic/genomic disorders.Addendum: Technical standards and guidelines: Molecular genetic testing for ultra-rare disorders
This document was retired by the American College of Medical Genetics and Genomics (ACMG) Board of Directors as of May 20, 2019 with the following addendum.Correction: 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)
The original article can be found online at https://doi.org/10.1038/s41436-019-0686-8 .Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)
To develop an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years.Direct-to-consumer prenatal testing for multigenic or polygenic disorders: a position statement of the American College of Medical Genetics and Genomics (ACMG)
A correction to this article is available online at https://doi.org/10.1038/s41436-021-01275-x .Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)
Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay–Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase “expanded carrier screening” is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology.Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Chromosomal microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism array, are widely applied in the diagnostic evaluation for both constitutional and neoplastic disorders. In a constitutional setting, this technology is accepted as the first-tier test for the evaluation of chromosomal imbalances associated with intellectual disability, autism, and/or multiple congenital anomalies. Furthermore, chromosomal microarray analysis is recommended for patients undergoing invasive prenatal diagnosis with one or more major fetal structural abnormalities identified by ultrasonographic examination, and in the evaluation of intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired.Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited.ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)
A correction to this article is available online at https://doi.org/10.1038/s41436-021-01278-8 .Incidental detection of acquired variants in germline genetic and genomic testing: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
With recent advances in DNA sequencing technology, it is now possible to begin to appreciate the full scope of DNA variation that arises over the course of an individual’s lifetime.1,2 Our understanding of how the human genome changes over time and in response to external exposures is growing with the improved availability of next-generation sequencing (NGS) based testing, including exome/genome sequencing of large patient cohorts. Clinical laboratories employing NGS-based methodologies can detect many types of DNA sequence variation including those that are present at a reduced variant allele fraction (VAF) (i.e., less than the 50% expected for a heterozygous germline finding).DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)
A comment to this article is available online at https://doi.org/10.1038/s41436-021-01141-w .DNA-based screening and personal health: a points to consider statement for individuals and health-care providers from the American College of Medical Genetics and Genomics (ACMG)
A comment to this article is available online at https://doi.org/10.1038/s41436-021-01141-w .Focused Revision: ACMG practice resource: Genetic evaluation of short stature
Addendum to: “ACMG practice guideline: Genetic evaluation of short stature”. Laurie H. Seaver, MD and Mira Irons, MD; ACMG Professional Practice and Guidelines Committee Genetics in Medicine 11:465–470 (2009); https://doi.org/10.1097/GIM.0b013e3181a7e8f8 ; published online 02 April 2009.Laboratory testing for fragile X, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Pathogenic variants in the FMR1 gene are associated with fragile X syndrome, fragile X–associated tremor ataxia syndrome (FXTAS), and fragile X–associated primary ovarian insufficiency (FXPOI). This document provides updated information regarding FMR1 pathogenic variants, including prevalence, genotype–phenotype correlations, and variant nomenclature. Methodological considerations are provided for Southern blot analysis and polymerase chain reaction (PCR) amplification of FMR1, including triplet repeat–primed and methylation-specific PCR.Laboratory analysis of acylcarnitines, 2020 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Acylcarnitine analysis is a useful test for identifying patients with inborn errors of mitochondrial fatty acid β-oxidation and certain organic acidemias. Plasma is routinely used in the diagnostic workup of symptomatic patients. Urine analysis of targeted acylcarnitine species may be helpful in the diagnosis of glutaric acidemia type I and other disorders in which polar acylcarnitine species accumulate. For newborn screening applications, dried blood spot acylcarnitine analysis can be performed as a multiplex assay with other analytes, including amino acids, succinylacetone, guanidinoacetate, creatine, and lysophosphatidylcholines.Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing
This is an addendum to the article available online at https://doi.org/10.1038/gim.2012.165 .Addendum: Statement on nutritional supplements and piracetam for children with Down syndrome
The original statement was published in the ACMG newsletter in 1996.Addendum: Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities
Addendum to: Genetics in Medicine 12:742–745 (2010) https://doi.org/10.1097/GIM.0b013e3181f8baad , published online 18 October 2010.Addendum: American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation
Addendum to: Genetics in Medicine7:650–654 (2005); https://doi.org/10.1097/01.gim.0000186545.83160.1e , published online 01 November 2005Treatment of mucopolysaccharidosis type II (Hunter syndrome): a Delphi derived practice resource of the American College of Medical Genetics and Genomics (ACMG)
Mucopolysaccharidosis, type II (MPS II, MIM 309900) is a severe lysosomal storage disease with multisystem involvement. There is one product approved by the FDA, an enzyme replacement therapy, based on a phase III trial in older, attenuated MPS II individuals. Guidance on treatment of MPS II is lacking, not only in general, but for specific clinical situations. A previous systematic evidence-based review of treatment for MPS II demonstrated insufficient strength in all data analyzed to create a definitive practice guideline based solely on published evidence.The interface of genomic information with the electronic health record: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Correction: Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing
An amendment to this paper has been published and can be accessed via a link at the top of the paper.Points to consider when assessing relationships (or suspecting misattributed relationships) during family-based clinical genomic testing: a statement of the American College of Medical Genetics and Genomics (ACMG)
Trio-based genetic analysis (typically involving a child and their biological parents) is an important tool in clinical diagnostic testing, as this type of analysis aids in developing an accurate understanding of the inheritance of variants observed in the proband.1-5 Understanding if a variant is inherited or is de novo can directly affect variant classification and result interpretation; consequently, misunderstanding the true biological relationship between analyzed samples can lead to erroneous clinical interpretations.CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods.Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG)
In 1980, Eric Engel1 first proposed the concept of uniparental disomy (UPD), in which both homologous chromosomes are inherited from one parent, with no contribution (for that chromosome) from the other parent. In 1988, the first case of a Mendelian disorder associated with UPD was reported, in which a child with cystic fibrosis (MIM 219700) had inherited two copies of a pathogenic variant in CFTR (MIM 602421) from a heterozygous carrier mother, with no contribution from the biological father.2Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG)
The sequencing of tumor-derived DNA to identify tumor-specific variations (biomarkers) with potential diagnostic, prognostic, or predictive therapeutic implications (hereafter, “tumor testing”) is a prominent example of precision medicine. Although the primary goal of this testing is the identification of biomarkers to guide patient management, testing tumor genomes also has the potential to uncover clinically relevant germline variation that is associated with heritable cancer susceptibility and other conditions, and carrier status for autosomal recessive disorders, if confirmed to be present in the germline.Risk categorization for oversight of laboratory-developed tests for inherited conditions: an updated position statement of the American College of Medical Genetics and Genomics (ACMG)
This document represents an update to the proposed approach of the American College of Medical Genetics and Genomics (ACMG) to categorize laboratory-developed tests (LDTs) for inherited conditions according to risk.1 Risk classification has historically been a determinant of whether, and to what extent, the US Food and Drug Administration (FDA) has overseen and regulated clinical tests. LDTs for constitutional variants continue to proliferate without a comprehensive federal regulatory framework in place.Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability
Exome and genome sequencing (ES/GS) are performed frequently in patients with congenital anomalies, developmental delay, or intellectual disability (CA/DD/ID), but the impact of results from ES/GS on clinical management and patient outcomes is not well characterized. A systematic evidence review (SER) can support future evidence-based guideline development for use of ES/GS in this patient population.Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)
Of all cancers that develop in women in the United States, breast cancer has the highest incidence, regardless of race or ethnicity, with an estimated 271,270 new cases and 42,260 deaths during 2019.1 Approximately 5–10% of breast cancers are estimated to result from hereditary causes, the majority of which are attributed to pathogenic or likely pathogenic (P/LP) variants in the BRCA1 and BRCA2 (BRCA1/2) genes, although other variants in genes such as PALB2, TP53, PTEN, CDH1, CHEK2, and ATM contribute.Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Peroxisomal disorders are a clinically and genetically heterogeneous group of diseases caused by defects in peroxisomal biogenesis or function, usually impairing several metabolic pathways. Peroxisomal disorders are rare; however, the incidence may be underestimated due to the broad spectrum of clinical presentations. The inclusion of X-linked adrenoleukodystrophy to the Recommended Uniform Screening Panel for newborn screening programs in the United States may increase detection of this and other peroxisomal disorders.The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)
Approximately 2–4% of pregnancies are complicated by significant fetal structural anomalies. Given respect for reproductive autonomy, all patients diagnosed with a fetal anomaly should be offered genetic counseling, including review of options for genetic testing.1 The prenatal testing strategy and test selection should be individualized and guided by prenatal imaging findings and family history. Current options include chromosomal studies by karyotyping, fluorescence in situ hybridization, and chromosomal microarray analysis (CMA) with consideration of targeted gene-specific molecular testing for suspected disorders.Diagnostic gene sequencing panels: from design to report—a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Gene sequencing panels are a powerful diagnostic tool for many clinical presentations associated with genetic disorders. Advances in DNA sequencing technology have made gene panels more economical, flexible, and efficient. Because the genes included on gene panels vary widely between laboratories in gene content (e.g., number, reason for inclusion, evidence level for gene–disease association) and technical completeness (e.g., depth of coverage), standards that address technical and clinical aspects of gene panels are needed.Laboratory screening and diagnosis of open neural tube defects, 2019 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Open neural tube defects (ONTDs) include open spina bifida (OSB) and anencephaly. These defects are caused by incomplete closure of the neural tube at about 4 weeks of pregnancy. Levels of early second-trimester maternal serum (ms) alpha-fetoprotein (AFP) are sufficiently elevated in affected pregnancies to be used as a population-based screening test. The basic screening methodology was described in the late 1970s and screening programs were active a few years later. By identifying pregnancies with the highest msAFP levels, about 80% of OSB and 95% of anencephaly can be identified as early as 16 weeks gestation.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)
Copy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing–based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health.Access to reproductive options after prenatal diagnosis—patient access and physician responsibilities: an updated position statement of the American College of Medical Genetics and Genomics (ACMG)
The American College of Medical Genetics and Genomics (ACMG) is concerned with the enactment of laws in some states that prevent or restrict access to termination of pregnancy after prenatal diagnosis of genetic disorders or congenital anomalies. The practice of medical genetics is predicated on the principle of providing patients with complete and accurate information on the condition that affects them, a member of their family, or an unborn fetus, and then discussing the management options that are available.Technical laboratory standards for interpretation and reporting of acquired copy-number abnormalities and copy-neutral loss of heterozygosity in neoplastic disorders: a joint consensus recommendation from the American College of Medical Genetics and Genomics (ACMG) and the Cancer Genomics Consortium (CGC)
The detection of acquired copy-number abnormalities (CNAs) and copy-neutral loss of heterozygosity (CN-LOH) in neoplastic disorders by chromosomal microarray analysis (CMA) has significantly increased over the past few years with respect to both the number of laboratories utilizing this technology and the broader number of tumor types being assayed. This highlights the importance of standardizing the interpretation and reporting of acquired variants among laboratories. To address this need, a clinical laboratory-focused workgroup was established to draft recommendations for the interpretation and reporting of acquired CNAs and CN-LOH in neoplastic disorders.The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG)
The American College of Medical Genetics and Genomics (ACMG) has previously published policy statements on the reporting of secondary findings in clinical exome and genome sequencing (ACMG SF v1.0 and ACMG SF v2.0), also known as the “ACMG 56” and “ACMG 59,” respectively.1,2 These recommendations specifically stated that “reporting some incidental [a.k.a. secondary] findings would likely have medical benefit for the patients and families of patients undergoing clinical sequencing” (ACMG board’s emphasis).Points to consider in the reevaluation and reanalysis of genomic test results: a statement of the American College of Medical Genetics and Genomics (ACMG)
Reductions in the cost of genomic analyses and the elimination of gene patents for clinical diagnostics have enabled clinical laboratories to provide increasingly comprehensive genetic testing using sequencing, microarrays, and other methods, resulting in the generation of a vast amount of data that then needs to be analyzed.1 A significant challenge for clinical laboratory geneticists is the provision of accurate and consistent variant classification. Variant classification has historically been hindered by a lagging recognition of gene–disease associations, as well as a lack of publicly available data (including reference data) from clinical laboratories and other sources.Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), β (PHKB), ɣ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone.Patient re-contact after revision of genomic test results: points to consider—a statement of the American College of Medical Genetics and Genomics (ACMG)
Nearly two decades ago, the American College of Medical Genetics (now the American College of Medical Genetics and Genomics [ACMG]) Policy Statement “Duty to re-contact” was prescient in highlighting the increasingly important issue of patient re-contact.1 Originally focused on clinical genetics practice, its importance now extends to both medical genomics and medical practice in general. Next-generation genomic testing, including multigene panels, exome sequencing (ES), and genome sequencing (GS), is permitting ever larger amounts of data to be collected on each patient sample, with a corresponding increase in the complexity of the results.Venous thromboembolism laboratory testing (factor V Leiden andfactor II c.*97G>A), 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Factor V Leiden and factor II c.*97G>A (formerly referred to asprothrombin 20210G>A) are the two most common genetic variants associated withvenous thromboembolism (VTE). Testing for these variants is one of the most commonreferrals in clinical genetics laboratories. While the methodologies for testingthese two variants are relatively straightforward, the clinical implementation canbe complicated with regard to test indications, risk assessment of occurrence andrecurrence of VTE, and related genetic counseling.Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Amino acid abnormalities are observed in a broad spectrum of inheritedmetabolic diseases, such as disorders of amino acid metabolism and transport,organic acidemias, and ureagenesis defects. Comprehensive analysis of physiologicamino acids in blood, urine, and cerebrospinal fluid is typically performed in thefollowing clinical settings: evaluation of symptomatic patients in whom a diagnosisis not known; evaluation of previously diagnosed patients to monitor treatmentefficacy; evaluation of asymptomatic or presymptomatic (at-risk) relatives of knownpatients; follow-up testing for an abnormal newborn screen; and assessment ofdietary protein adequacy or renal function in general patient populations.Currently, the most common analytical method to quantify amino acids is based on ionexchange chromatography using post-column derivatization with ninhydrin andspectrophotometric detection.Insuring patient access and affordability for treatments for rare and ultrarare diseases: a policy statement of the American College of Medical Genetics and Genomics
The past decade has seen tremendous progress in the development of new drugs for patients with genetic disorders, including cystic fibrosis, many lysosomal storage disorders (Gaucher disease, Fabry disease, mucopolysaccharidoses, and others) and most recently, Duchenne muscular dystrophy and spinal muscular atrophy (SMA). These new drugs are specialty drugs, and the projected cost of these new treatments is staggering. For example, the projected cost for the first year of treatment with nusinersen (SpiranzaTM) for SMA is $750,000, and $350,000 per year after that.Yield of additional genetic testing after chromosomal microarray for diagnosis of neurodevelopmental disability and congenital anomalies: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
Chromosomal microarray (CMA) is recommended as the first-tier test in evaluation of individuals with neurodevelopmental disability and congenital anomalies. CMA may not detect balanced cytogenomic abnormalities or uniparental disomy (UPD), and deletion/duplications and regions of homozygosity may require additional testing to clarify the mechanism and inform accurate counseling. We conducted an evidence review to synthesize data regarding the benefit of additional testing after CMA to inform a genetic diagnosis.Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
The purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life.Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Pediatric clinical exome/genome sequencing and the engagement process: encouraging active conversation with the older child and adolescent: points to consider—a statement of the American College of Medical Genetics and Genomics (ACMG)
As exome and genome sequencing become more widely incorporated into clinical pediatric care, it becomes increasingly important to encourage a robust engagement process with the mature older child and adolescent patient to facilitate meaningful conversation that can aid in the complex decision-making and return of findings process around genomic testing. A dialogue that promotes this engagement process is best attained when the clinician shares salient information, including the relatively distinct implications of the test, while listening and responding to the child’s evolving perspectives as well as the parent(s)’ concerns (“parent” used broadly throughout to include guardians and others who act in this capacity for the genetics encounter).Laboratory analysis of organic acids, 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
Organic acid analysis detects accumulation of organic acids in urine and other body fluids and is a crucial first-tier laboratory test for a broad spectrum of inborn errors of metabolism. It is also frequently ordered as follow-up for a positive newborn screen result, as recommended by American College of Medical Genetics and Genomics newborn screening ACTion sheets and algorithms. The typical assay is performed by gas chromatography–mass spectrometry. These technical standards were developed to provide guidance for laboratory practices in organic acid analysis, interpretation, and reporting.Considerations in healthcare reform for patients and families with genetic diseases: a statement of the American College of Medical Genetics and Genomics
Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers, to help them provide quality medical genetic services. Adherence to these recommendations does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Professional responsibilities regarding the provision, publication, and dissemination of patient phenotypes in the context of clinical genetic and genomic testing: points to consider—a statement of the American College of Medical Genetics and Genomics (ACMG)
Disclaimer: This Points to Consider document is designed as an educational resource to provide best practices for medical genetic clinicians, laboratories, and journals regarding the provision, publication, and dissemination of patient phenotypes in the context of genomic testing, clinical genetic practice, and research. While the goal of the document is the improvement of patient care, the considerations and practices described should not be considered inclusive of all proper considerations and practices or exclusive of others that are reasonably directed to obtaining the same goal.Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG)
Disclaimer: These ACMG Standards and Guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these Standards and Guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results.Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics
Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these Standards and Guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen.Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG)
Disclaimer: ACMG Clinical Laboratory Practice Resources are developed primarily as an educational tool for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these practice resources is voluntary and does not necessarily assure a successful medical outcome. This Clinical Laboratory Practice Resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results.Genome editing in clinical genetics: points to consider—a statement of the American College of Medical Genetics and Genomics
Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers, to help them provide quality medical genetic services. Adherence to these recommendations does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Laboratory and clinical genomic data sharing is crucial to improving genetic health care: a position statement of the American College of Medical Genetics and Genomics
Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers, to help them provide quality medical genetic services. Adherence to these recommendations does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics
Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical services. Adherence to these recommendations is completely voluntary and does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results.Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics
Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen.Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics
Disclaimer: This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Section E6.1–6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow–acquired chromosomal abnormalities
Disclaimer: These American College of Medical Genetics and Genomics standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results.Section E6.5–6.8 of the ACMG technical standards and guidelines: chromosome studies of lymph node and solid tumor–acquired chromosomal abnormalities
Disclaimer: These ACMG standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results.Direct-to-consumer genetic testing: a revised position statement of the American College of Medical Genetics and Genomics
Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Scope of practice: a statement of the American College of Medical Genetics and Genomics (ACMG)
Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics
These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Disclaimer: These ACMG Standards and Guidelines were developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results.A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment
Disclaimer: The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue and is the result of a review and analysis of current professional literature believed to be reliable.ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing
Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease
Huntington disease is an autosomal-dominant neurodegenerative disease of mid-life onset caused by expansion of a polymorphic trinucleotide (CAG) repeat. Variable penetrance for alleles carrying 36–39 repeats has been noted, but the disease appears fully penetrant when the repeat numbers are >40. An abnormal CAG repeat may expand, contract, or be stably transmitted when passed from parent to child. Assays used to diagnose Huntington disease must be optimized to ensure the accurate and unambiguous quantitation of CAG repeat length.Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics
This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss
Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of a hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals.Phenylalanine hydroxylase deficiency: diagnosis and management guideline
Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life.ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)
Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner.ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013
Microarray methodologies, including array comparative genomic hybridization and single-nucleotide polymorphism–detecting arrays, are accepted as an appropriate first-tier test for the evaluation of imbalances associated with intellectual disability, autism, and multiple congenital anomalies. This technology also has applicability in prenatal specimens. To assist clinical laboratories in validation of microarray methodologies for constitutional applications, the American College of Medical Genetics and Genomics has produced the following revised professional standards and guidelines.ACMG statement on access to reproductive options after prenatal diagnosis
19 July 2013—Bethesda, MD—The American College of Medical Genetics and Genomics (ACMG) is concerned with the enactment of laws in some states that prevent or restrict access to termination of pregnancy after prenatal diagnosis of genetic disorders or congenital anomalies. The practice of medical genetics is predicated on the principle of providing patients with accurate information on the genetic disorder or congenital anomaly that affects them, a member of their family, or an unborn fetus, and then discussing the management options that are available.ACMG clinical laboratory standards for next-generation sequencing
Next-generation sequencing technologies have been and continue to be deployed in clinical laboratories, enabling rapid transformations in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude, and continuous advances are being made. It is now feasible to analyze an individual’s near-complete exome or genome to assist in the diagnosis of a wide array of clinical scenarios. Next-generation sequencing technologies are also facilitating further advances in therapeutic decision making and disease prediction for at-risk patients.Points to consider for informed consent for genome/exome sequencing
In its recently released report, “ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing,” the American College of Medical Genetics and Genomics (ACMG) created a set of recommendations addressing incidental findings and a minimum list of conditions, genes, and variants that are recommended to be returned whenever clinical sequencing is performed. The ACMG recommended that, for the conditions on the list, the laboratory should return the incidental findings to the doctor ordering the sequencing, and those doctors should manage this information with the patient in the context of that patient’s clinical presentation and family history.Incidental findings in clinical genomics: a clarification
On 22 March 2013, the American College of Medical Genetics and Genomics (ACMG) released a practice statement entitled “ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.”1 We firmly stated our view that there is a subset of conditions/genes/variants for which there is the significant potential for preventing disease morbidity and mortality if identified in the presymptomatic period. Commentaries about the ACMG recommendations have raised a number of concerns that prompt us to clarify five issues raised in the recommendations: (i) patient autonomy, (ii) incidental findings in children, (iii) clinical laboratory considerations, (iv) result communication, and (v) prediction of disease likelihood.ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics
Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Mutations in the FMR1 gene are associated with fragile X syndrome, fragile X tremor ataxia syndrome, and premature ovarian insufficiency. This document provides updated information regarding FMR1 gene mutations, including prevalence, genotype–phenotype correlation, and mutation nomenclature. Methodological considerations are provided for Southern blot analysis and polymerase chain reaction amplification of the FMR1 gene, including triplet repeat–primed and methylation-specific polymerase chain reaction.ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing
In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results.ACMG position statement on prenatal/preconception expanded carrier screening
For years, clinicians have offered gene-by-gene carrier screening to patients and couples considering future pregnancy or those with an ongoing pregnancy early in gestation. Examples include ethnic-specific screening offered to Ashkenazi Jewish patients and panethnic screening for cystic fibrosis and spinal muscular atrophy. Next-generation sequencing methods now available permit screening for many more disorders with high fidelity, quick turnaround time, and lower costs. However, instituting these technologies carries with it perils that must be addressed.American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders
Microarray methodologies, to include array comparative genomic hybridization and single-nucleotide polymorphism–based arrays, are innovative methods that provide genomic data. These data should be correlated with the results from the standard methods, chromosome and/or fluorescence in situ hybridization, to ascertain and characterize the genomic aberrations of neoplastic disorders, both liquid and solid tumors. Over the past several decades, standard methods have led to an accumulation of genetic information specific to many neoplasms.ACMG statement on noninvasive prenatal screening for fetal aneuploidy
Noninvasive assessment of the fetal genome is now possible using next-generation sequencing technologies. The isolation of fetal DNA fragments from maternal circulation in sufficient quantity and sizes, together with proprietary bioinformatics tools, now allows patients the option of noninvasive fetal aneuploidy screening. However, obstetric care providers must become familiar with the advantages and disadvantages of the utilization of this approach as analysis of cell-free fetal DNA moves into clinical practice.Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions
The autism spectrum disorders are a collective of conditions that have in common impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased dramatically over the past two decades. In addition, increased attention has been paid to these conditions by both lay and professional groups. These trends have resulted in an increase in the number of referrals to clinical geneticist for the evaluation of persons with autism spectrum disorders.Risk categorization for oversight of laboratory-developed tests for inherited conditions
This document represents the proposed approach of the American College of Medical Genetics and Genomics (ACMG) to classify laboratory-developed tests for inherited conditions. Risk classification has been the determinant of whether or not medical tests are overseen and regulated by the US Food and Drug Administration (FDA). Therefore, because laboratory-developed tests for germline mutations continue to proliferate without sound regulatory frameworks in place, an ACMG-appointed workgroup of laboratorians and clinicians considered the medical risks and implications resulting from germline mutation analysis in a variety of contexts to develop the proposed approach.Technical report: ethical and policy issues in genetic testing and screening of children
The genetic testing and genetic screening of children are commonplace. Decisions about whether to offer genetic testing and screening should be driven by the best interest of the child. The growing literature on the psychosocial and clinical effects of such testing and screening can help inform best practices. This technical report provides ethical justification and empirical data in support of the proposed policy recommendations regarding such practices in a myriad of settings.Genet Med 2013:15(3):234–245ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing
MTHFR polymorphism testing is frequently ordered by physicians as part of the clinical evaluation for thrombophilia. It was previously hypothesized that reduced enzyme activity of MTHFR led to mild hyperhomocysteinemia which led to an increased risk for venous thromboembolism, coronary heart disease, and recurrent pregnancy loss. Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous thromboembolism.American College of Medical Genetics and Genomics: standards and guidelines for documenting suspected consanguinity as an incidental finding of genomic testing
Genomic testing, including single-nucleotide polymorphism–based microarrays and whole-genome sequencing, can detect long stretches of the genome that display homozygosity. The presence of these segments, when distributed across multiple chromosomes, can indicate a familial relationship between the proband’s parents. This article describes the detection of possible consanguinity by genomic testing and the factors confounding the inference of a specific parental relationship. It is designed to guide the documentation of suspected consanguinity by clinical laboratory professionals and to alert laboratories to the need to establish a reporting policy in conjunction with their ethics review committee and legal counsel.Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy
Tamoxifen, a widely prescribed drug for the treatment and prevention of breast cancer, is metabolized to more potent metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme. Variants in the CYP2D6 gene can cause patients to be either intermediate or poor metabolizers, thereby rendering tamoxifen treatment less effective. Testing for CYP2D6 gene variants is available in Clinical Laboratory Improvement Amendments–certified clinical laboratories; however, the biological complexity of the variants makes result interpretation and phenotype prediction challenging.
