Interpretation Of Genetic Test Results Research Articles

The Role of Genetic Testing in Adult CKD

Mounting evidence indicates that monogenic disorders are the underlying cause in a significant proportion of chronic kidney disease patients. In recent years, the diagnostic yield of genetic testing in these patients has increased significantly as a result of revolutionary developments in genetic sequencing techniques and sequencing data analysis. Identification of disease-causing genetic variant(s) in chronic kidney disease patients may facilitate prognostication and personalized management, including nephroprotection and decisions around kidney transplantation, and is crucial for genetic counseling and reproductive family planning. A genetic diagnosis in a chronic kidney disease patient allows for screening of at-risk family members, which is also important for determining their eligibility as kidney transplant donors. Despite evidence for clinical utility, increased availability, and data supporting the cost-effectiveness of genetic testing in chronic kidney disease, especially when applied early in the diagnostic process, many nephrologists do not use genetic testing to its full potential because of multiple perceived barriers. Our aim in this paper is to empower nephrologists to (further) implement genetic testing as a diagnostic means in their clinical practice, based on the most recent insights and exemplified by patient vignettes. We stress why genetic testing is of significant clinical benefit to many chronic kidney disease patients, provide recommendations for which patients to test and which test(s) to order, give guidance about interpretation of genetic testing results, and highlight the necessity for and essential components of pre- and post-test genetic counseling.

Classification of germline variants identified in cancer predisposition genetic testing - consensus of the CZECANCA consortium.

Hereditary cancer syndromes are an important subset of malignant cancers caused by pathogenic variants in one of many known cancer predisposition genes. Diagnosis of cancer predisposition is based on genetic testing using next-generation sequencing. This allows many genes to be analysed at once, increasing the number of variants identified. The correct classification of the variants found is essential for the clinical interpretation of genetic test results. The aim of this study is to summarise the rules for classifying identified variants within individual laboratories and to present the process for creating a common classification. In the Czech Republic, the sharing of identified genetic variants and the development of their consensus classification among national laboratory diagnostic communities is carried out within the Czech Cancer Panel for Clinical Application (CZECANCA) consortium of scientific and diagnostic oncogenetic laboratories. Consensus for variant classification follows a defined protocol. Sharing the results and consensus classification accelerates and refines the release of genetic test results, harmonises results between laboratories and thus contributes to improving the care of individuals at high risk of cancer and their relatives.

Diagnostic Challenges in ABCA4-Associated Retinal Degeneration: One Gene, Many Phenotypes

(1) Purpose: ABCA4-associated retinal degeneration (ABCA4-RD) is a phenotypically diverse disease that often evades diagnosis, even by experienced retinal specialists. This may lead to inappropriate management, delayed genetic testing, or inaccurate interpretation of genetic testing results. Here, we illustrate the phenotypic diversity of ABCA4-RD using a series of representative cases and compare these to other conditions that closely mimic ABCA4-RD. (2) Methods: Genetically confirmed ABCA4-RD cases with representative phenotypes were selected from an inherited retinal disease cohort in Singapore and compared to phenocopies involving other retinal diseases. (3) Results: ABCA4-RD phenotypes in this series included typical adolescent-onset Stargardt disease with flecks, bull’s eye maculopathy without flecks, fundus flavimaculatus, late-onset Stargardt disease, and severe early-onset Stargardt disease. Phenocopies of ABCA4-RD in this series included macular dystrophy, pattern dystrophy, cone dystrophy, advanced retinitis pigmentosa, Leber congenital amaurosis, drug toxicity, and age-related macular degeneration. Key distinguishing features that often suggested a diagnosis of ABCA4-RD were the presence of peripapillary sparing, macular involvement and centrifugal distribution, and a recessive pedigree. (4) Conclusions: ABCA4-RD demonstrates a remarkable phenotypic spectrum that makes diagnosis challenging. Awareness of the clinical spectrum of disease can facilitate prompt recognition and accurate diagnostic testing.

Critical components of genomic medicine practice for non-genetics healthcare professionals: Genetic counselors' perspectives and implications for medical education.

Genetic services are increasingly provided by non-genetics healthcare professionals (NGHPs) with minimal formal training in genetics/genomics. Research demonstrates gaps in knowledge and clinical practices in genetics/genomics among NGHPs, but there is a lack of consensus on the specific knowledge needed by NGHPs to effectively provide genetic services. As clinical genetics professionals, genetic counselors (GCs) have insight into the critical components of genetics/genomics knowledge and practices needed by NGHPs. This study explored GCs' beliefs regarding whether NGHPs should provide genetic services and identified GCs' perceptions of the components of knowledge and clinical practice in genetics/genomics that are most critical for NGHPs providing genetic services. Two hundred and forty GCs completed an online quantitative survey with 17 participating in a follow-up qualitative interview. Descriptive statistics and cross-comparisons were generated for survey data. Interview data were analyzed using an inductive qualitative method for cross-case analysis. Most GCs disagreed with NGHPs providing genetic services, but beliefs varied widely, ranging from disagreement due to perceived gaps in knowledge or clinical skills to acceptance of NGHPs providing genetic services due to limited access to genetics professionals. Across survey and interview data, GCs endorsed the interpretation of genetic test results, understanding implications of results, collaboration with genetics professionals, knowledge of the risks and benefits to testing, and recognizing indications for genetic testing as critical components of knowledge and clinical practice for NGHPs. Several recommendations for improving the provision of genetic services were provided by respondents including educating NGHPs to provide genetic services through case-based continuing medical education and increasing collaboration between NGHPs and genetics professionals. As GCs are healthcare providers with experience and vested interests in educating NGHPs, their perspectives can help inform the creation of continuing medical education to ensure patients' access to high-quality genomic medicine care from providers of varying backgrounds.

Dissecting the Knowns for the Unknowns: Refining the Classification of Genomic Variations in Hematological Diseases By the Clingen Hematological Cancer Taskforce (HCT)

Genomic variants are important diagnostic, prognostic and/or therapeutic markers in hematological malignancies. However, substantial interlaboratorydiscrepancy in interpretation and reporting of these variants creates challenges. To provide a reliable clinical reference and assist the consistent interpretation of genomic variations, the Hematological Cancer Taskforce (HCT) was formed under the ClinGen Somatic Cancer Clinical Domain Working Group in 2020 with a goal to standardize the systematic curation, evidence-based clinical interpretation and reporting of somatic genetic variations found in hematological cancers. A team of multi-disciplinary experts, including genomic scientists, oncologists, hematopathologists, molecular pathologists, clinical lab directors, and biocurators with expertise in hematological malignancies, were recruited to evaluate the genomic alterations seen in hematological malignancies according to the AMP/ASCO/CAP and/or the ClinGen/CGC/VICC guidelines (PMIDs: 27993330, 35101336). The HCT identified FLT3 variants as the highest priority for curation and clinical interpretation efforts based on the immediate and strong clinically actionable implications of FDA-approved FLT3 inhibitors. A ClinGen FLT3 Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to focus on curation of FLT3 tyrosine kinase domain (TKD) variants and is now developing FLT3-specific classification guidelines. FLT3-ITD (internal tandem duplication) and TKD (D835/I836) are the most frequent FLT3 variants with well-established prognostic and therapeutic significance and predict response to Midostaurin and Gilteritinib, FDA-approved drugs for newly diagnosed and relapsed/ refractory AML, respectively. The FLT3SC-VCEP classified their assertions of the FLT3-ITD and D835 variants as Tier 1 - level A in CIViC following the AMP/ASCO/CAP guideline. The interpretation of the rest of FTL3 TKD variants including D835 were less consistent. A pilot assessment to apply the ClinGen/CGC/VICC oncogenicity standards has classified the following D835 variants as oncogenic (OS2, OS3, OP1, OP4): c.2505T>A (Asp835Glu), c.2503G>T (Asp835Tyr), c.2503G>C (Asp835His), and c.2504A>T (Asp835Val); one variant as likely oncogenic: c.2028C>A (Asn676Lys) (OS2, OM4, OP4); and one variant of uncertain significance (VUS): c.2503_2504delinsAT (Asp835Ile) (OM1, OP1, OP3, OP4). Assessment of additional FLT3 variants is underway with the goal to refine FLT3-specific rules to classify FLT3 variants using the AMP/ASCO/CAP guidelines and the ClinGen/CGC/VICC oncogenicity classification standards as a framework. Published evidence using FDA-approved tests simultaneously evaluating the TKD variants in amino acids D835 or I836 often do not specify the affected codon. Due to the high prevalence of D835 variants in AML, the clinical significance of I836 variants is much less studied. In addition to curation from the literature, the FLT3 SC-VCEP is leveraging their international expertise by performing a multi-institutional deidentified data collection for I836 variants from individual laboratories to assess therapeutic response and oncogenicity. Due to the critical need for consistent and standardized interpretation of genetic test results, the HCT aims at developing gene-specific recommendations to standardize the reporting and interpretation of somatic variants and plans to expand ClinGen SC-VCEPs in additional gene-disease domains.

Neurological diseases: A perspective genetic approach & dietary intervention

Neurological diseases account for a large and increasing health burden worldwide and most vexing afflictions known to mankind. This is since neurological problems are often terrible to patients and their families because the great majority of neurological and neurodegenerative conditions lack effective treatments. There is a plethora of neurological conditions such as Parkinson's, Huntington’s, and Alzheimer’s disease etc. To estimate the rising neurological burden due to genetic or non-genetic (Environmental) factors, DALYs (Disability-Adjusted Life Years) are an essential indicator for estimating the worldwide burden. A systematic and comprehensive data analysis of neurological diseases within the Indian population has warranted that in India prevalence and incidence of neurological diseases is doubled from 4.0% (95 percent UI 3.2-5.0) in 1990 to 8.2% (6.6%-10.2%) in 2019. Several variables contribute to the onset and progression of neurological diseases, including oxidative stress, inflammation, metal imbalances, microbiome, as well as genetic and nutritional factors. Therefore urgently needed to develop new and more effective genetic and therapeutic strategies to combat these devastating diseases. This review demonstrated the increasing global public health importance of neurodegenerative diseases with the help of a new era of omics, influence of dietary intervention, adequate dietary choices as part of a continuation of healthy lifestyle choices, genetic testing, interpretation of genetic testing results, and genetic counseling may help to reduce the risk and may help to decrease the burden of neurological problems.

A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian, and colorectal cancer susceptibility genes.

10512 Background: Up to 10% of all cancers are attributable to germline mutations and identifying mutation carriers is critical for cancer prevention. Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) with unknown impact on health, which can be clarified through reclassification. However, there is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, racial/ethnic differences, and the proportion of patients who undergo cancer preventive healthcare management as a result of VUS reclassification. Methods: Retrospective analysis of persons carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer genes who underwent genetic counseling at four geographically dispersed cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019, and followed until 2020. Results: Among 2,715 individuals, 3,261 VUS and 313 P/LP variants were reported and 11% (300/2,715) had a P/LP in addition to VUS. In total, 8.1% of all individuals with VUS experienced reclassifications, 87.1% of which were downgraded to benign or likely benign and 12.9% were upgraded to P/LP. Reclassification rates varied significantly among cancer care settings from 4.81% to 20.19% (overall p < 0.001). The reclassification pattern across genes suggests that VUS in most genes underwent reclassification at a rate proportional to their prevalence in the overall sample and occurred commonly in ATM, BRCA2, BRCA1, and CHEK2. Compared to their prevalence in the sample, reclassification rates were higher for Blacks (13.6% vs 19.0%), lower for Asians (6.3% vs 3.5%), and proportional for Whites and Hispanics. Median time to reclassification decreased steadily between 2014 and 2019 from 3.08 to 0.91 years. Overall, 11.3% of all reclassified VUS resulted in clinically actionable findings and 4.6% subsequently changed individuals’ clinical managements including prophylactic surgeries and intensive screenings for cancer prevention and early detection. Conclusions: In this large multisite study, VUS reclassification changed clinical management for 0.4% of all individuals. VUS reclassification may alter clinical management, has implications for precision cancer prevention, and highlights the need for standardized clinical practice guidelines and policies for returning reclassified results to patients.

Familial Mediterranean Fever: How to Interpret Genetic Results? How to Treat? A Quarter of a Century After the Association with the Mefv Gene

To provide an up-to-date approach to diagnosis and management of FMF patients. Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and prototype monogenic autoinflammatory recurrent fever syndrome. Although it is one of the well-known autoinflammatory disorders, evaluations in the etiopathogenesis and genetics of the disease have shown that FMF is more complex than previously known. Since the number of reported MEFV variants increased, evaluating the genetic test results has become more challenging. Here, we suggest a roadmap for clinicians to facilitate their decisions regarding diagnosis, treatment, and follow-up in FMF patients with different genotype-phenotype combinations. The correct interpretation of genetic test results is crucial for timely diagnosis, appropriate treatment, and follow-up of FMF patients.

Character of cell-free genomic DNA in embryo culture medium and the prospect of its clinical application in preimplantation genetic testing

Abstract There is increasing evidence that cell-free DNA (cfDNA) in spent culture media (SCM) can be amplified for genetic testing. Therefore, this paper reviews the characteristics of cfDNA, including its fragment size, amount, origin, as well as some factors affecting the success rate of its amplification, together to provide researchers with a more comprehensive perspective on embryonic cfDNA. The origin of cfDNA in SCM is complicated and poses challenges to the interpretation of genetic test results. Advanced molecular techniques should distinguish between embryonic and contaminated DNA to maximize the success rate of amplification and analysis. Recent data showed that the type of culture medium, assisted hatching or not, the type of amplification kit, and fresh or thawed embryos were not related to the success rate of amplification, but the length of culture time might affect the success rate. The longer culture time, the more cfDNA is available in the SCM. Then we focused on the concordance between trophectoderm (TE), inner cell mass, whole embryo, and embryonic cfDNA. Despite successful amplification, the concordance between TE and embryonic cfDNA was low. In summary, non-invasive genetic testing using SCM could represent a major advance in future single embryo selection, however, contamination and timing for media collection are key factors affecting the results, and current noninvasive cfDNA testing should not be directly applied to clinical practice. Further research is needed to improve the methods used for testing techniques and genetic analysis to achieve greater accuracy and trace its origins before it can be used in the clinics.

PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

Role of Clinical Genetic Testing in the Management of Aortopathies.

Thoracic aortic aneurysms (TAA) have a strong heritable basis, and identification of a genetic etiology has important implications for patients with TAA and their relatives. This review provides an overview of Mendelian causes of TAA, discusses important considerations for genetic testing, and summarizes the impact a genetic diagnosis may have on a patient's medical care. Thoracic aortic disease may be non-syndromic or seen as part of a genetic syndrome, such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome. Expanded access to genetic testing has revealed the wide and overlapping phenotypic spectrum of these conditions, highlighting the need for genetic testing to establish an accurate diagnosis. Important aspects of genetic evaluation include thorough phenotyping through family history and physical examination, selection of an appropriate genetic test driven by the patient's phenotype, and careful interpretation of genetic test results. Improved understanding of the natural history of these conditions has led to tailored management recommendations, including gene-based recommendations for prophylactic surgical repair. Identification of a genetic etiology allows for careful monitoring of disease progression, informs the timing of prophylactic surgical repair, and facilitates the identification of other at-risk relatives through cascade genetic testing.

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.

Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis. This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication. In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 (PKP2) were shown to reclassify less frequently as compared with other genes (PKP2, n=1, 8.3%; desmosomal non-PKP2, n=20, 66.7%; nondesmosomal, n=26, 68.4%; P=0.001for overall comparison; PKP2 versus desmosomal non-PKP2, P=0.001; PKP2 versus nondesmosomal, P<0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants. Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.

Survey on Physicians’ Knowledge and Training Needs in Genetic Counseling in Germany

Background: In recent years, germline testing of women with a risk of developing breast and ovarian cancer has increased rapidly. This is due to lower costs for new high-throughput sequencing technologies and the manifold preventive and therapeutic options for germline mutation carriers. The growing demand for genetic counseling meets a shortfall of counselors and illustrates the need to involve the treating clinicians in the genetic testing process. This survey was undertaken to assess their state of knowledge and training needs in the field of genetic counseling and testing. Methods: A cross-sectional survey within the European Bridges Study (Breast Cancer Risk after Diagnostic Gene Sequencing) was conducted among physician members (n = 111) of the German Cancer Society who were primarily gynecologists. It was designed to examine their experience in genetic counseling and testing. Results: Overall, the study revealed a need for training in risk communication and clinical recommendations for persons at risk. One-third of respondents communicated only relative disease risks (31.5%) instead of absolute disease risks in manageable time spans. Moreover, almost one-third of the respondents (31.2%) communicated bilateral and contralateral risk-reducing mastectomy as an option for healthy women and unilateral-diseased breast cancer patients without mutations in high-risk genes (e.g. BRCA1 or BRCA2). Most respondents expressed training needs in the field of risk assessment models, the clinical interpretation of genetic test results, and the decision-making process. Conclusion: The survey demonstrates a gap of genetic and risk literacy in a relevant proportion of physicians and the need for appropriate training concepts.

Assessing the strength of evidence for genes implicated in fatty acid oxidation disorders using the ClinGen clinical validity framework

Newborn screening is an incredibly useful tool for the early identification of many metabolic disorders, including fatty acid oxidation (FAO) disorders. In many cases, molecular tests are necessary to reach a final diagnosis, highlighting the need for a thorough evaluation of genes implicated in FAO disorders. Using the ClinGen (Clinical Genome Resource) clinical validity framework, thirty genes were analyzed for the strength of evidence supporting their association with FAO disorders. Evidence was gathered from the literature by biocurators and presented to disease experts for review in order to assign a clinical validity classification of Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Reported Evidence. Of the gene-disease relationships evaluated, 22/30 were classified as Definitive, three as Moderate, one as Limited, three as No Reported Evidence and one as Disputed. Gene-disease relationships with a Limited, Disputed, and No Reported Evidence were found on two, six, and up to four panels out of 30 FAO disorder-specific panels, respectively, in the National Institute of Health Genetic Testing Registry, while over 70% of the genes on panels are definitively associated with an FAO disorder. These results highlight the need to systematically assess the clinical relevance of genes implicated in fatty acid oxidation disorders in order to improve the interpretation of genetic testing results and diagnosis of patients with these disorders.

Establishment of Specialized Clinical Cardiovascular Genetics Programs: Recognizing the Need and Meeting Standards: A Scientific Statement From the American Heart Association

Cardiovascular genetics is a rapidly evolving subspecialty within cardiovascular medicine, and its growth is attributed to advances in genome sequencing and genetic testing and the expanding understanding of the genetic basis of multiple cardiac conditions, including arrhythmias (channelopathies), heart failure (cardiomyopathies), lipid disorders, cardiac complications of neuromuscular conditions, and vascular disease, including aortopathies. There have also been great advances in clinical diagnostic methods, as well as in therapies to ameliorate symptoms, slow progression of disease, and mitigate the risk of adverse outcomes. Emerging challenges include interpretation of genetic test results and the evaluation, counseling, and management of genetically at-risk family members who have inherited pathogenic variants but do not yet manifest disease. With these advances and challenges, there is a need for specialized programs combining both cardiovascular medicine and genetics expertise. The integration of clinical cardiovascular findings, including those obtained from physical examination, imaging, and functional assessment, with genetic information allows for improved diagnosis, prognostication, and cascade family testing to identify and to manage risk, and in some cases to provide genotype-specific therapy. This emerging subspecialty may ultimately require a new cardiovascular subspecialist, the genetic cardiologist, equipped with these combined skills, to permit interpretation of genetic variation within the context of phenotype and to extend the utility of genetic testing. This scientific statement outlines current best practices for delivering cardiovascular genetic evaluation and care in both the pediatric and the adult settings, with a focus on team member expertise and conditions that most benefit from genetic evaluation.

Precision Medicine in Internal Medicine.

Medicine has long sought to match diagnostic and treatment approaches to the particular needs and risks of individual patients. The decreasing cost and increasing ease of genetic sequencing have propelled the rise of precision medicine. Precision medicine aims to use genetic and other information to provide care tailored to the individual patient, with the goal of improving clinical outcomes and minimizing unnecessary diagnostic and therapeutic interventions. Although developments in genetic sequencing have the potential to transform clinical care, there are important limitations, including uncertainty in the clinical interpretation of many genetic variants and concerns about privacy, discrimination, and cost. To help clinicians understand the basics of genetic sequencing and how to apply it in clinical practice, Annals of Internal Medicine is launching a new "Precision Medicine" series. This introduction provides a general overview of clinical sequencing, with a focus on germline variation. Subsequent articles will use a case-based format to provide concise summaries of specific clinical precision medicine scenarios that are relevant to the practice of internal medicine. These cases will highlight specific clinical indications; interpretation of genetic test results; and ethical, legal, cost, and privacy issues related to genetic testing. The goal is to provide practical information on the appropriate application and interpretation of genomics in routine clinical practice.

Congenital muscular dystrophy a case study with a mutation in the POMT1 gene

Background: The congenital muscular dystrophies (CMD) are a group of heterogeneous diseases, manifested with a wide variety of clinical findings. Dystroglycanopathy is regarded as a subgroup among the CMD group of diseases. POMT1 mutations that cause alpha-dystroglycan hypoglycolization are reported to cause CMD diseases with autosomal recessive inheritance pattern. Case Presentation: A 14-year-old girl patient was referred with classical symptoms for CMDs. Whole exome sequencing (WES) analysis revealed a mutation in the POMT1 gene after the differential diagnosis of the patient. A homozygous mutation detected in the patient diagnosed muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 1 (OMIM 613155). Conclusion: Different mutations in the POMT1 gene have been found to cause three different types of diseases (CMDs). The differential diagnosis for these diseases clinically remains difficult, as a result, detailed clinical evaluation of patients becomes mandatory. Also, a multidisciplinary and collaborative approach involving complete clinical information and anamnesis is essential for the interpretation of genetic test results for such complex disorders.

Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center

ObjectiveThe contemporary practice of testing for genetically triggered aortic and arterial aneurysms and dissections is not well described. This study aimed to describe this practice at a tertiary care academic center and to ascertain the yield of testing in establishing the diagnosis in patients referred on the basis of clinical suspicion. MethodsThis is a retrospective cohort study of patients referred for vascular genetic testing at an academic medical center between 2010 and 2015. Patients were identified by Current Procedural Terminology diagnostic codes 81405, 81408, and 81479 for genetic testing (Marfan syndrome, Loeys-Dietz syndrome, aneurysms-osteoarthritis syndrome, COL3A1, and familial thoracic aortic aneurysm panel [ACTA2, COL3A1, TGFBR1, TGFBR2, SMAD3, TGFB2, MYLK, MYH11, and PRKG1 genes]) and by review of the collagen vascular laboratory database for genetic testing results. Data abstracted included demographics, clinical history, reason for referral, family history, referring provider type, and outcomes of genetic testing. ResultsNinety-six patients (44.3% male; median age, 40.8 years) were referred for suspected genetic vascular disease. Genetic testing was performed in 75 cases thought to have heritable mutations related to aortic or arterial aneurysms and dissections. The most common reason for genetic testing was a personal history of aortic or arterial aneurysms and dissections (62.3%; mean age, 45.8 ± 11.1 years), followed by a family history of aortic or arterial aneurysms and dissections without a personal history (26.6%; age, 28.8 ± 17.9 years). The most common genetic testing performed was a familial thoracic aortic aneurysm gene panel (44%), followed by single gene testing for vascular Ehlers-Danlos syndrome (33.3%). Genetic testing identified a pathogenic mutation in 36% of the cases. The highest likelihood of identifying a pathogenic mutation was in those who had a family history with an already diagnosed mutation (57.1%), followed by patients with aortic root and ascending aortic aneurysm or dissection (42.3%). ConclusionsIn patients with suspected genetically triggered vascular disease, the yield of clinical vascular genetic testing is reasonable when selective genetic testing is performed on the basis of personal or family history. These tests should be obtained with appropriate expertise in genetic counseling and interpretation of genetic testing results. Negative genetic test results in the setting of a positive family history demonstrate the limits of testing and known mutations leading to genetically triggered aortic and arterial aneurysms and dissections and support the need for novel gene discovery.