Interpretation Of Genetic Testing Research Articles

The Elusive Nature of ABCC8-related Maturity-Onset Diabetes of the Young (ABCC8-MODY). A Review of the Literature and Case Discussion.

Maturity-onset diabetes of the young (MODY) are monogenic forms of diabetes resulting from genetic defects, usually transmitted in an autosomal dominant fashion, leading to β-cell dysfunction. Due to the lack of homogeneous clinical features and univocal diagnostic criteria, MODY is often misdiagnosed as type 1 or type 2 diabetes, hence its diagnosis relies mostly on genetic testing. Fourteen subtypes of MODY have been described to date. Here, we review ABCC8-MODY pathophysiology, genetic and clinical features, and current therapeutic options. ABCC8-MODY is caused by mutations in the adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene, involved in the regulation of insulin secretion. The complexity of ABCC8-MODY genetic picture is mirrored by a variety of clinical manifestations, encompassing a wide spectrum of disease severity. Such inconsistency of genotype-phenotype correlation has not been fully understood. A correct diagnosis is crucial for the choice of adequate treatment and outcome improvement. By targeting the defective gene product, sulfonylureas are the preferred medications in ABCC8-MODY, although efficacy vary substantially. We illustrate three case reports in whom a diagnosis of ABCC8-MODY was suspected after the identification of novel ABCC8 variants that turned out to be of unknown significance. We discuss that careful interpretation of genetic testing is needed even on the background of a suggestive clinical context. We highlight the need for further research to unravel ABCC8-MODY disease mechanisms, as well as to clarify the pathogenicity of identified ABCC8 variants and their influence on clinical presentation and response to therapy.

Identification of an ultra-rare Alu insertion in the CFTR gene: Pitfalls and challenges in genetic test interpretation

Cystic fibrosis (CF) is a life-limiting genetic disorder characterized by defective chloride ion transport due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Early detection through newborn screening programs significantly improves outcomes for individuals with CF by enabling timely intervention. Here, we report the identification of an Alu element insertion within the exon 15 of CFTR gene, initially overlooked in standard next-generation sequencing analyses. However, using traditional molecular techniques, based on polymerase chain reaction and Sanger sequencing, allowed the identification of the Alu element and the reporting of a correct diagnosis. Our analysis, based on bioinformatics tools and molecular techniques, revealed that the Alu element insertion severely affects the gene expression, splicing patterns, and structure of CFTR protein. In conclusion, this study emphasizes the importance of how the integration of human expertise and modern technologies represents a pivotal step forward in genomic medicine, ensuring the delivery of precision healthcare to individuals affected by genetic diseases.

Patient Experiences and Challenges in the Management of Autoinflammatory Diseases-Data from the International FMF & AID Global Association Survey.

Autoinflammatory diseases (AIDs) are rare, mostly genetic diseases that affect the innate immune system and are associated with inflammatory symptoms. Both paediatric and adult patients face daily challenges related to their disease, diagnosis and subsequent treatment. For this reason, a survey was developed in collaboration between the FMF & AID Global Association and the Erlangen Center for Periodic Systemic Autoinflammatory Diseases. The aim of the survey was to collect the personal assessment of affected patients with regard to their current status in terms of diagnostic timeframes, the interpretation of genetic tests, the number of misdiagnoses, and pain and fatigue despite treatment. In total, data from 1043 AID patients (829 adults and 214 children/adolescents) from 52 countries were collected and analyzed. Familial Mediterranean fever (FMF) (521/50%) and Behçet's disease (311/30%) were the most frequently reported diseases. The average time to diagnosis was 3 years for children/adolescents and 14 years for adults. Prior to the diagnosis of autoinflammatory disease, patients received several misdiagnoses, including psychosomatic disorders. The vast majority of patients reported that genetic testing was available (92%), but only 69% were tested. A total of 217 patients reported that no increase in acute-phase reactants was detected during their disease episodes. The intensity of pain and fatigue was measured in AID patients and found to be high. A total of 88% of respondents received treatment again, while 8% reported no treatment. AID patients, particularly adults, suffer from significant delays in diagnosis, misdiagnosis, and a variety of symptoms, including pain and fatigue. Based on the results presented, raising awareness of these diseases in the wider medical community is crucial to improving patient care and quality of life.

The genetics of autosomal dominant familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common genetic conditions. Affected individuals are unable to metabolize cholesterol due to inherited changes in the low-density lipoprotein (LDL) receptor, which impairs the ability to metabolize cholesterol, resulting in extremely high levels of cholesterol that leads to premature coronary artery disease. Autosomal dominant FH is caused by variants in several genes, which may present as heterozygous FH (less severe) or homozygous FH (more severe). Clinical diagnosis may be more likely when there is a family history of two or more first-degree relatives with total and LDL-cholesterol (LDL-C) level elevations, a child is identified, or the affected individual or close relatives have tendon xanthomas and/or progressive atherosclerosis. This article provides an overview of autosomal dominant FH, including disease prevalence, clinical diagnostic criteria, genetic variants, diagnostic testing, pathognomonic findings, and treatment options. It also shares a brief case, which highlights challenges associated with genetic test interpretation and the importance of including experienced providers in the diagnosis and treatment of this underdiagnosed and often untreated or undertreated genetic condition.

Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships—allelic requirement, inheritance modes, and disease mechanisms

PurposeThe terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework. MethodsTerminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. ResultsWe present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources. ConclusionThe terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Assessment of medical knowledge toward genetic testing for individuals with hereditary breast and ovarian cancer syndrome in Brazil

Genetic testing has become increasingly used in medical practice to enable genetic cancer risk assessment. In Hereditary Breast and Ovarian Cancer syndrome (HBOC), it can be used to screen pathogenic germline variants. The access to early diagnosis, from the request until the proper interpretation of genetic tests depends on medical knowledge. The aim of this study was to evaluate the knowledge of family physicians, oncologists, geneticists and gynecologists regarding genetic testing for patients with suspected HBOC in Brazil. A cross-sectional survey of physicians was performed using a self-administered questionnaire. One hundred and ninety-two physicians answered the questionnaire (23 were geneticists, 38 gynecologists, 39 family physicians, and 92 oncologists). Only 15.4% of family physicians and 26% of gynecologists feel prepared to order genetic testing for patients with personal and/or family history of breast and/or ovarian cancer. Even though 87% of the oncologists have genetic testing available in their clinical practice, only 51.1% consider they have sufficient knowledge to manage patients after detecting a pathogenic germline variant and 17.4% do not feel comfortable interpreting them. Most oncologists and geneticists are very knowledgeable about recommendations for genetic testing order and management of HBOC patients. On the other hand, gynecologists and family physicians order genetic testing less frequently (28.9% and 7.7%, respectively) and have difficulties interpreting (26.3% and 2.3%, respectively) and managing these patients. These observations raise important issues regarding the implementation of genetic testing in Brazil, including the development of training programs for physicians from different specialties.

Barriers to diversity in cancer therapy: Uncovering disparities in knowledge and interpretation of genetic testing among African Americans, and their direct implications for access to mutation-based therapies.

e18587 Background: African American cancer patients are disproportionately impacted by limited access to health education and resources, limiting their access to advanced care and clinical trials (CTs). In line, African Americans have the highest death rate and shortest survival of any racial/ethnic group in the US for most cancers. In this study we analyzed cancer patients’ knowledge of different parameters of their disease, including biomarker/mutational status knowledge which is vital for making informed treatment decisions. Methods: Leal (formerly, Trialjectory) is an AI-based platform that matches cancer patients to CTs based on a self reported medical profile. The profile includes parameters essential for CT matching including disease status, stage, biomarker/mutational status, treatment history, comorbidities and demographics. This study included a multi-racial sample cohort of 11,302 patients with advanced cancer who completed the questionnaire between 2019-2023. We characterized the general questionnaire completion rate and further focused on whether genetic testing was performed and on biomarker knowledge across varying clinical, demographic and racial/ethnic groups. Results: The general questionnaire completion rate was not affected by age, gender, or ethnic group. Genetic testing performance was associated with cancer types for which treatment guidelines recommend testing. There was no major difference in genetic testing performance between ethnic groups (Pearson’s Χ² = 0.05), with slightly lower rates in African Americans compared to other racial groups. A notable gap was found in the interpretation and reporting of test results across all races. Race and ethnic background had a significant impact on biomarker knowledge (Pearson’s Χ² < 0.0001), with African Americans having a profoundly lower probability of knowing/reporting their mutation status compared to other races/ethnic groups. Clinical trials that require the presence of certain mutations for a match were ranked lower on the matched CT list or were not matched at all for patients who failed to report their biomarker data. Conclusions: African Americans are less likely to know or interpret/report their mutation status compared to other races or ethnic groups. This disparity was not influenced by the completion rate of the questionnaire, suggesting that ethnicity is not a hindrance to accessing technology. Our results highlight a significant gap in access to information and education particularly in regards to biomarker knowledge, which play a crucial role in obtaining the most effective treatment or accessing mutation-specific targeted therapy within or outside of a CT. Addressing these disparities is imperative to ensure that cancer patients can make informed treatment decisions.

Web Exclusive. Annals On Call - Reinterpreted Genetic Tests.

In this episode of Annals On Call, Dr. Centor discusses the obligation of physicians to follow up with patients no longer in their care when genetic test interpretation changes with Dr. Paul Appelbaum.

Genetics and clinics: together to diagnose cardiomyopathies.

The diagnostic paths of hereditary cardiomyopathies (CMPs) include both clinical and molecular genetics. The first step is the clinical diagnosis that guides the decisions about treatments, monitoring, prognostic stratification, and prevention of major events. The type of CMP [hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy (ARVC)] is defined by the phenotype, and the genetic testing may identify the precise cause. Furthermore, genetic testing provides a pre-clinical diagnosis in unaffected family members and the basis for prenatal diagnosis. It can contribute to risk stratification (e.g. LMNA) and can be a major diagnostic criterion (e.g. ARVC). The test can be limited to a single gene when the pre-test diagnostic hypothesis is based on proven clinical evidence (e.g. GLA for Fabry disease). Alternatively, it can be expanded from a multigene panel to a whole exome or whole genome sequencing when the pre-test hypothesis is a genetically heterogeneous disease. In the last decade, the study of larger genomic targets led to the identification of numerous gene variants not only pathogenic (clinically actionable) but also of uncertain clinical significance (not actionable). For the latter, the pillar of the genetic diagnosis is the correct interpretation of the pathogenicity of genetic variants, which is evaluated using both bioinformatics and clinical-genetic criteria about the patient and family. In this context, cardiologists play a central role in the interpretation of genetic tests, performing the deep-phenotyping of variant carriers and establishing the co-segregation of the genotype with the phenotype in families.

Distance learning training in genetics and genomics testing for Italian health professionals: results of a pre and post-test evaluation


 Background
 Progressive advances in technologies for DNA sequencing and decreasing costs are allowing an easier diffusion of genetic and genomic tests. Physicians’ knowledge and confidence on the topic is often low and not suitable for manage this challenge. Tailored educational programs are required to reach a more and more appropriate use of genetic technologies.
 Methods
 A distance learning course has been created by experts from different Italian medical associations with the support of the Italian Ministry of Health. The course was directed to professional figures involved in prescription and interpretation of genetic tests. A pretest-post-test study design was used to assess knowledge improvement. We analyzed the proportion of correct answers for each question pre and post-test, as well as the mean score difference stratified by gender, age, professional status and medical specialty.
 Results
 We reported an improvement in the proportion of correct answers for 12 over 15 questions of the test. The overall mean score to the questions significantly increased in the post-test, from 9.44 to 12.49 (p-value < 0.0001). In the stratified analysis we reported an improvement in the knowledge of all the groups except for geneticists; the pre-course mean score of this group was already very high and did not improve significantly.
 Conclusion
 Distance learning is effective in improving the level of genetic knowledge. In the future, it will be useful to analyze which specialists have more advantage from genetic education, in order to plan more tailored education for medical professionals.

Pharmacists on mental health teams benefit youth

COVID-19 has intensified the “mental health pandemic,” said Julie Dopheide, PharmD, BCPP, FASHP. What’s worse is that access to mental health care continues to be a challenge for individuals. Dopheide and coauthors of a new paper published in Child and Adolescent Psychiatric Clinics of North America believe that clinical pharmacy is underutilized within the mental health space. In the paper, the authors share how clinical pharmacists and psychiatric pharmacists can improve care for children and adolescents with mental health diagnoses. “Youth are increasingly prescribed psychiatric medications, and they are vulnerable to drug interactions and adverse effects and need special monitoring and education on the benefits and potential risks of psychiatric medication,” said Dopheide, who is a professor of clinical pharmacy, psychiatry, and the behavioral sciences at the University of Southern California School of Pharmacy and Keck School of Medicine in Los Angeles. Dopheide said job opportunities for mental health pharmacists, particularly BCPPs, are increasing nationwide. BCPS and BCACP pharmacists also have a role in mental health, she noted. “Mental health settings are inherently multidisciplinary and psychiatric treatment teams are very open to clinical pharmacy,” said Dopheide. While some psychotropic medications are prescribed off-label to youth, many commonly prescribed medications have been studied in this age group with clear labeling on dosing and monitoring to ensure they can be given safely. “Pharmacists need to actively stay abreast of which psychiatric medications are the most well-studied in youth so these can be recommended over off-label, less well-studied mental health medications,” said Dopheide. A 2015 study from the Office of the Inspector General (OIG) on youth prescribing of antipsychotics in 5 states found that two-thirds of the 485 medical records reviewed demonstrated quality-of-care concerns, including poor monitoring (53%) and inappropriate treatment (41%). OIG and FDA even warn that children and adolescents need metabolic syndrome monitoring when prescribed antipsychotic medications. Research has found higher rates of sedation, weight gain, tachycardia, and agitation in youth given psychotropics compared with adults. Not only does evidence point to an increased risk for type 2 diabetes in youth taking antipsychotics, but emerging evidence suggests this is also the case with SSRIs given to youth. However, some county and state mental health departments are waking up to this and partnering with pharmacists to improve medication therapy monitoring. Several states—including Texas, Indiana, and California—have published pediatric psychotropic guidelines or practice parameters developed through collaborations between child psychiatrists and psychiatric pharmacists to elevate the quality of care for children and adolescents. Many states include child psychiatrists collaborating with pharmacists on Medicaid pharmacy and therapeutics committees and drug utilization review boards to improve medication safety. Clinical pharmacists are not regularly involved in mental health treatment teams even though they’ve been able to improve the quality of care for patients. “While medication management is an important component of the care plan, unfortunately, due to limited resources for mental health, the pharmacist is often not included in the mental health care team,” said Debbie Lu, PharmD, MPH, lead author of the paper and assistant professor at Touro University California College of Pharmacy. Psychiatry teams are more likely to hire therapists or case workers as their allied health staff. However, there are health systems, such as Kaiser Permanente, that have benefited from having dedicated mental health pharmacists on the team. The paper presents case studies in different settings to show how a collaboration with a psychiatrist and pharmacist can work in real life. “A psychiatric pharmacist can review medication administration records and screen for drug interactions to discuss with the child psychiatrist and child fellows,” said Dopheide. “The psychiatric pharmacist can participate in daily treatment planning to bring up pertinent drug therapy issues, such as the need for monitoring for metabolic syndrome or hyperprolactinemia with antipsychotics.” Another common way child psychiatrists and clinical pharmacists collaborate is through medication groups for patients and families. Also, interpretation of genetic tests and creation of pediatric guidelines for psychiatric medications is another “real-life” way these providers can collaborate. Payment for these services remains a challenge for pharmacists, but Dopheide said health system administration can justify paying for a psychiatric pharmacist through improved medication outcomes, like better adherence, follow-up, and prevention of adverse drug reactions or interactions. “In many health systems, billing for medication groups and medication reviews is a way to pay for integration of psychiatric pharmacists,” Dopheide said.

Current and Future Approaches to Classify VUSs in LGMD-Related Genes.

Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a major challenge in genetic test interpretation and disease diagnosis. Understanding the phenotypic consequences of VUSs can provide clinical guidance regarding LGMD risk and therapy. In this review, we provide a brief overview of the subtypes of LGMD, disease diagnosis, current classification systems for investigating VUSs, and a potential deep mutational scanning approach to classify VUSs in LGMD-related genes.

Exome Sequencing Highlights a Potential Role for Concealed Cardiomyopathies in Youthful Sudden Cardiac Death.

Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident. Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (46 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, N=141 456 individuals]) nonsynonymous variants identified in 24 Clinical Genome Resource adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines. Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; P=0.05) SCA survivors and 8 out of 68 (11.8%; P=0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, P<0.02) SUD cases without ventricular fibrosis. Our data further supports the inclusion of strong evidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.

Integration of Genomics Data and Electronic Health Records Toward Personalized Medicine: A Targeted Review

Introduction: Integration of rapidly expanding high-throughput omics technologies and electronic health record (EHR) has created an unprecedented advantage in terms of acquiring routine healthcare data to accelerate genetic discovery. In this regard, EHR can also provide several important advantages to omics research if the integration challenges are well handled. The main purpose of the present study was to review available and published knowledge in the related literature and then to classify and discuss stakeholders’ requirements in this domain.Material and Methods: At first, a broad electronic search of all available literature in English was conducted on the topic through a search in the databases of Medline, Web of Science, Institute of Electrical and Electronics Engineers (IEEE), Scopus, and Cochrane. Then, stakeholders’ requirements were tabulated, and finally, a word cloud was generated and analyzed to achieve functional and non-functional cases.Results: A total of 81 articles were included in the given analysis. Integration requirements also consisted of nine functional cases including a uniform approach to the interpretation of genetic tests, standardized terminologies and ontologies, structured data entry as much as possible, an integrated online patient portal, multiple data source handling, machine-readable storing and reporting, research-oriented requirements, pharmacogenomics decision support capabilities, and phenotyping algorithms and knowledge base. Besides, there were three non-functional cases comprised of interoperability of multiple systems, ethical, legal, security factor, and big data computations.Conclusion: The main challenges in this way could also have semantic and technical themes. Therefore, system developers could guarantee the success of systems by overcoming the given challenges.

Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice.

The overall diagnostic yield of massively parallel sequencing–based tests in patients with chronic kidney disease (CKD) is 30% for paediatric cases and 6–30% for adult cases. These figures should encourage nephrologists to frequently use genetic testing as a diagnostic means for their patients. However, in reality, several barriers appear to hinder the implementation of massively parallel sequencing–based diagnostics in routine clinical practice. In this article we aim to support the nephrologist to overcome these barriers. After a detailed discussion of the general items that are important to genetic testing in nephrology, namely genetic testing modalities and their indications, clinical information needed for high-quality interpretation of genetic tests, the clinical benefit of genetic testing and genetic counselling, we describe each of these items more specifically for the different groups of genetic kidney diseases and for CKD of unknown origin.

A Case-Based Approach to Understanding Complex Genetic Information in an Evolving Landscape.

The rapid integration of highly sensitive next-generation sequencing technologies into clinical oncology care has led to unparalleled progress, and yet these technological advances have also made genetic information considerably more complex. For instance, accurate interpretation of genetic testing for germline/inherited cancer predisposition syndromes and somatic/acquired pathogenic variants now requires a more nuanced understanding of the presence and incidence of clonal hematopoiesis and circulating tumor cells, with careful evaluation of pathogenic variants occurring at low variant allele frequency required. The interplay between somatic and germline pathogenic variants and awareness of distinct genotype-phenotype manifestations in various inherited cancer syndromes are now increasingly appreciated and can impact patient management. Through a case-based approach, we focus on three areas of particular relevance to the treating clinician oncologist: (1) understanding clonal hematopoiesis and somatic mosaicism, which can be detected on germline sequencing and lead to considerable confusion in clinical interpretation; (2) implications of the detection of a potentially germline pathogenic variant in a high-penetrance cancer susceptibility gene during routine tumor testing; and (3) a review of gene-specific risks and surveillance recommendations in Lynch syndrome. A discussion on the availability and difficulties often associated with direct-to-consumer genetic testing is also provided.

Knowing More Than the Knowns in Familial Hypercholesterolemia

Not all genetic testing is the same, and interpretation of genetic testing gains accuracy when a patient’s ancestry is considered. In this issue of JAMA Cardiology, Sturm and colleagues1 explore these issues for familial hypercholesterolemia (FH) genetic testing.

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.The American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has the mission of maintaining high technical standards for the performance and interpretation of genetic tests. In part, this is accomplished by the publication of the document ACMG Technical Standards for Clinical Genetics Laboratories, which is now maintained online (http://www.acmg.net). This subcommittee also reviews the outcome of national proficiency testing in the genetics area and may choose to focus on specific diseases or methodologies in response to those results. Accordingly, the subcommittee selected fragile X syndrome to be the first topic in a series of supplemental sections, recognizing that it is one of the most frequently ordered genetic tests and that it has many alternative methods with different strengths and weaknesses. This document is the fourth update to the original standards and guidelines for fragile X testing that were published in 2001, with revisions in 2005 and 2013, respectively.This versionClarifies the clinical features associated with different FMRI variants (Section 2.3)Discusses important reporting considerations (Section 3.3.1.3)Provides updates on technology (Section 4.1)

Consumer Testing for Disease Risk: ACOG Committee Opinion Summary, Number 816.

With the increased emphasis on patient-driven health care and readily available access to patients as consumers through the internet and media, many genetic testing companies are marketing directly to consumers. Direct-to-consumer genetic testing may result in unique concerns and considerations, because of limited knowledge about available genetic tests among patients and health care professionals, challenges in interpretation of genetic test results, and lack of oversight of some companies, as well as issues of privacy and confidentiality. It is important to note that tests from different companies that evaluate the same condition or genes can vary greatly in scope and technical quality. When undergoing direct-to-consumer genetic testing, the consumer should be apprised of risk from screening or susceptibility test results that can neither prove nor eliminate disease potential but may be distressing for consumers. Because of these considerations and the fact that the interpretation of test results often requires specific training and medical knowledge, direct-to-consumer genetic testing ideally should be performed after counseling to review the test's potential benefits, risks, and limitations. Confirmatory genetic testing should be performed under the supervision of an appropriate obstetrician-gynecologist or other health care professional who is skilled in interpretation of genetic testing and risk assessment for the diseases of interest. This Committee Opinion has been updated to include information on counseling for patients who present with direct-to-consumer genetic test results, clinical vignettes, and an overview of currently available testing options as well as those potentially available in the near future.

Consumer Testing for Disease Risk: ACOG Committee Opinion, Number 816.

With the increased emphasis on patient-driven health care and readily available access to patients as consumers through the internet and media, many genetic testing companies are marketing directly to consumers. Direct-to-consumer genetic testing may result in unique concerns and considerations, because of limited knowledge about available genetic tests among patients and health care professionals, challenges in interpretation of genetic test results, and lack of oversight of some companies, as well as issues of privacy and confidentiality. It is important to note that tests from different companies that evaluate the same condition or genes can vary greatly in scope and technical quality. When undergoing direct-to-consumer genetic testing, the consumer should be apprised of risk from screening or susceptibility test results that can neither prove nor eliminate disease potential but may be distressing for consumers. Because of these considerations and the fact that the interpretation of test results often requires specific training and medical knowledge, direct-to-consumer genetic testing ideally should be performed after counseling to review the test's potential benefits, risks, and limitations. Confirmatory genetic testing should be performed under the supervision of an appropriate obstetrician-gynecologist or other health care professional who is skilled in interpretation of genetic testing and risk assessment for the diseases of interest. This Committee Opinion has been updated to include information on counseling for patients who present with direct-to-consumer genetic test results, clinical vignettes, and an overview of currently available testing options as well as those potentially available in the near future.