Use Of Multigene Panels Research Articles

Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline.

To guide use of multigene panels for germline genetic testing for patients with cancer. An ASCO Expert Panel convened to develop recommendations on the basis of a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing. Fifty-two guidelines and consensus statements met eligibility criteria for the primary search; 14 studies were identified for Clinical Question 4. Patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered. When considering what genes to include in the panel, the minimal panel should include the more strongly recommended genes from Table 1 and may include those less strongly recommended. A broader panel may be ordered when the potential benefits are clearly identified, and the potential harms from uncertain results should be mitigated. Patients who meet criteria for germline genetic testing should be offered germline testing regardless of results from tumor testing. Patients who would not normally be offered germline genetic testing based on personal and/or family history criteria but who have a pathogenic or likely pathogenic variant identified by tumor testing in a gene listed in Table 2 under the outlined circumstances should be offered germline testing.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.

Genetic testing for familial melanoma.

While the average lifetime risk of melanoma worldwide is approximately 3%, those with inherited high-penetrance mutations face an increased lifetime risk of 52-84%. In countries of low melanoma incidence, such as in Southern Europe, familial melanoma genetic testing may be warranted when there are two first degree relatives with a melanoma diagnosis. Testing criteria for high incidence countries such as USA, or with very-high incidence, such as Australia and New Zealand, would require a threshold of 3 to 4 affected family members. A mutation in the most common gene associated with familial melanoma, CDKN2A, is identified in approximately 10-40% of those meeting testing criteria. However, the use of multi-gene panels covering additional less common risk genes can significantly increase the diagnostic yield. Currently, genetic testing for familial melanoma is typically conducted by qualified genetic counsellors, however with increasing demand on testing services and high incidence rate in certain countries, a mainstream model should be considered. With appropriate training, dermatologists are well placed to identify high risk individuals and offer melanoma genetic test in dermatology clinics. Genetic testing should be given in conjunction with pre- and post-test consultation. Informed patient consent should cover possible results, the limitations and implications of testing including inconclusive results, and potential for genetic discrimination. Previous studies reporting on participant outcomes of genetic testing for familial melanoma have found significant improvements in both sun protective behavior and screening frequency in mutation carriers.

Impact of non-BRCA genes in the indication of risk-reducing surgery in hereditary breast and ovarian cancer syndrome (HBOC)

Hereditary breast and ovarian cancer syndrome (HBOC) is associated with other genes beyond BRCA. The performance of prophylactic bilateral mastectomy (PBM) and risk-reducing salpingo-oophorectomy (RRSO) are primary prevention measures that can be recommended depending on the type of pathogenic/likely pathogenic (P/LP) variant detected or family history. Descriptive, retrospective, and observational audit. Between the years 2015 to May 2023, a total of 288 families were studied by a multigene panel using NGS. Statistical analysis was performed using IBM SPSS Statistics 22. Non-BRCA P/LP variants were detected in 38 families (84.2% females and 15.8% males); 18 in ATM (44.7 %), 7 in CHEK2 (18.4%), 5 in TP53 (13.2%), 2 in PTEN (5.3%), 2 in PALB2 (5.3%), 1 in RAD51C (2.6%), 1 in BRIP1 (2.6%), 1 in CDH1 (2.6%) and 1 in RAD51D (2.6%). Risk-reducing surgery was recommended in 18 patients (PBM in 18 [46.2 %] and RRSO in 5 [13.2%]). Given the results of our study, we support the recommendations of the guidelines on the use of multigene panels in the study of HBOC. Knowing P/LP variants beyond BRCA1 and 2 has an impact on the follow-up and primary and secondary prevention of affected families.

Real-world biomarker testing trends in metastatic non-small cell lung cancer (NSCLC).

e18728 Background: NSCLC is now recognized as not one disease, but many—differentiated by an increasing number of molecular targets. About 50% of patients with advanced nonsquamous NSCLC have a targetable driver mutation. We retrospectively assessed biomarker testing trends in a large community oncology practice to identify evolving real-world testing rates and patterns in the areas of methodology, specimen types, and vendors. Methods: Natural-language processing queries were used to extract data from biomarker testing reports of patients diagnosed with stage IV NSCLC in 2015-2019. Tests were included if done within 1 year of diagnosis and were classified as NGS panels (20+ genes) or targeted single-gene tests. Results: Records of 587 patients were included. Over the 5-year study window, testing rates increased for all 6 mutations analyzed (Table). In 2015, only ALK, ROS1, and EGFR were profiled in our data (n = 20 patients), all using targeted single-gene tests. The use of multigene panels increased steadily over time, constituting the majority by 2019. MET, RET, and NTRK were tested almost exclusively using NGS panels (data beginning in 2016). Tissue-only specimens were used for 93.8% of patients diagnosed in 2015, while tissue plus blood were used in 6.3%. Blood-only samples began appearing in our data in 2016, making up 7% of patients. By 2019, the use of blood tests had increased substantially, to 47% of patients, although tissue-only remained the most common type (54%). While blood testing has become more popular, it is often still performed with tissue tests. The primary testing methods used in 2015-2017 were FISH for ALK and ROS1; NGS for MET, NTRK, and RET; and Sanger or NGS for EGFR. By 2018, NGS had become the predominant test method across all 6 biomarkers. During 2015-2016, several vendors were used for testing, with a very segmented market for ALK and EGFR tests. By 2019, the market had aligned to a few key vendors for the majority of tests. In 2016, the top 5 vendors did 76% of 180 total tests, which increased to 93% of 1880 tests in 2019. Almost all blood testing in our data was performed by a single vendor. Conclusions: Testing rates for ALK, ROS1, and EGFR were more consistent than those for MET, RET, and NTRK throughout the study window, possibly because of earlier availability of tests and treatments for these biomarkers. NGS was more available by the time MET, RET, and NTRK became established as actionable biomarkers, explaining the earlier use of panels. A limitation is that nearly 75% of the data are from the final 2 years. These results, however, represent notable testing trends from a large practice and illustrate the expanding application of molecular testing in community oncology.[Table: see text]

EP430: Genetics professionals’ perspectives on the reporting of Variants of Uncertain Significance (VUS): Should they always be reported?

Variants of uncertain significance (VUS) are common. With increasing use of multi-gene panels (MGP), the numbers of VUS grow. Not all VUS have the same degree of uncertainty, presenting challenges to non-genetics healthcare providers (HCPs), patients and families. We report the results of a survey assessing attitudes of genetics professionals on the return of VUS results from MGP, emphasizing cancer genetics professionals in academic settings.

Predictive molecular genetic tests in clinical oncology

Molecular genetic testing is an essential component of modern practical oncology. It is aimed at individualized therapy prescription and can significantly improve the life expectancy of patients. The analyzed molecular events include alterations affecting single genes (EGFR, KRAS, etc.), as well as integral characteristics of tumor genome, for example, total tumor mutation burden (TMB) or deficiency of certain types of DNA repair (microsatellite instability, homologous DNA recombination deficiency, etc.). The spectrum of clinically relevant genetic markers continues to expand, and some of them acquire the status of "agnostic", i.e., applicable to tumors of various origin. As a consequence, there is a trend toward substitution of individual gene testing with the use of multigene panels allowing simultaneous assessment of all significant predictive markers.

Detection and impact of genetic disease in a level IV neonatal intensive care unit.

To determine detection rates of genetic disease in a level IV neonatal intensive care unit (NICU) and cost of care. We divided 2703 neonates, admitted between 2013 and 2016 to a level IV NICU, into two epochs and determined how genetic testing utilization, genetic diagnoses identified, and cost of NICU care changed over time. The increasing use of multi-gene panels 104 vs 184 (P = 0.02) and whole exome sequencing (WES) 9 vs 28 (P = 0.03) improved detection of genetic disease, 9% vs 12% (P < 0.01). Individuals with genetic diagnoses had higher mean NICU charges, $723,422 vs $417,013 (P < 0.01) secondary to longer lengths of stay, not genetic services. The increased utilization of broad genetic testing improved the detection of genetic disease but contributed minimally to the cost of care while bolstering understanding of the patient's condition and prognosis.

Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients.

The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options. The aim of this study was to present data that demonstrate the different levels of actionability for multi-gene panels used in genetic testing of breast cancer patients and their family members. We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing. We reviewed positive results in respect of risk estimation and management, cascade family testing, secondary findings and information for treatment decision-making. A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high, moderate, low and with insufficient evidence for breast cancer risk genes, respectively. Six point seven percent of individuals were double heterozygotes. Germline findings in 92% of individuals are linked to evidence-based treatment information and risk estimates for predisposition to breast and/or other cancer types. The use of germline findings for treatment decision making expands the indication of genetic testing to include individuals that could benefit from targeted treatments.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study.

Simple SummaryGastric cancer is one of the most common cancers worldwide, showing high mortality rates. A small portion of gastric cancer patients, known as early onset gastric cancer (EOGC) patients, develop the disease before age 50, and their characteristics are poorly described. Thus, our main objective was to describe the clinical, molecular, and genetic characteristics of EOGC in a large multicenter cohort of patients. We were able to identify that most EOGC cases have similar characteristics: diagnosed at advanced stage, diffuse type, and infrequent DNA mismatch repair somatic deficiency. Although familial aggregation of gastric cancer was uncommon, a germline genetic mutation was identified in 25% of the patients tested. Our results show that EOGC has a marked genetic heterogeneity. Thus, it is essential to consider familial history of tumors, not only GC, in order to select adequate patients to perform a suitable genetic counseling and enhance the emerging use of multigene panels. Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.

The importance of variants of unknown significance (VUS) in BRCA mutation.

e22507 Background: Genetic testing of patients for BRCA mutation may report variants of unknown significance (VUS). The use of multi-gene panels in clinical care has been increasing. Consequently, the reporting of variants of unknown significance has also increased. More than two decades of research and testing have elevated the status of BRCA1 and BRCA2 genes as the most well characterized genes. However, VUS are found even in BRCA1/2 testing. This raises many ethical and policy issues including communicating the significance of the results and possible clinical management options to patients. The practicing physicians would face the ethical and potential legal burden of contacting and explaining to patients, when any role of VUS changes and gets reclassified as potentially harmful. Methods: Data were collected retrospectively from medical records of patients tested for BRCA mutations. The results of fifty-two patients were analyzed. Eight patients had BRCA1 and BRCA2 mutations and twelve patients had variants of unknown significance. Results: When the results of thirteen patients with BRCA mutations with VUS were analyzed further, the variants included POLE, CHEK2, PALB2, MUTHYH, BR1P1, MSH3, ATM, RAD51C, GALNT12, etc. The age of these patients ranged from 39 years to 69 years. Four patients had ovarian cancer and eight patients had breast cancer, and one patient had both breast and ovarian cancers. The number of patients with stage IV, III, II, and I diseases were six, one, two, and two respectively. One patient had bilateral breast cancer and one patient had carcinoma in-situ. Eight patients had family histories of various cancers, including cancers of the breast, uterine, and prostate cancer. All patients were treated appropriately and three patients died due to their disease. Conclusions: Based on patients’ age, family histories, and disease characteristics BRCA mutation analyses were done. All patients tested positive for BRCA mutations and VUS were informed about their results. Variants of BRCA1 and BRCA2 occur in 2%-4% of tests depending on the laboratories, where the tests were performed. There is no concordance as to how VUS results were reported. There is conflicting evidence regarding the pathogenicity of VUS. These make clinical recommendations very complex. Based on existing guidelines, physicians can explain the details of the significance of BRCA! And BRCA2 mutations to patients with clarity. However, it is difficult and unclear to give recommendations regarding prophylactic measures, specific treatment options for BRCA mutation positive breast and ovarian cancer, follow-ups, and family testing in patients with VUS. Therefore, during BRCA testing, when VUS are reported routinely along with mutations of known significance, the treating physicians would need a better guidance to advise their patients without unduly increasing their anxiety, fear, and potential for misunderstanding.

315P High-penetrance breast and/or ovarian cancer susceptibility genes in Filipinos

Breast cancer is the most common cancer seen in women worldwide. In the Philippines, 24,798 cases of breast cancer were diagnosed in 2018, making up 17.6% of 141,021 newly diagnosed cases of cancer in the country. Genetic counseling and testing for hereditary cancers is a relatively new undertaking for medical oncologists in the Philippines. Previous studies show that prevalence of BRCA mutations in Filipinos is 5.1% to 6.8%, which is consistent with data found in the Asian population. However, no studies have yet been done looking at multigene panel testing for Filipino patients who meet the testing criteria for high-penetrance breast and/or ovarian cancer susceptibility genes. From September 2019 to May 2020, we did multigene panel testing (Invitae Multi-Cancer Panel) for patients who met the testing criteria for high-penetrance breast and/or ovarian cancer susceptibility genes (NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020 – December 4, 2019). We tested 24 patients (23 females, 1 male; 29-81 years old), including 14 with breast cancer, 4 with ovarian cancer, 1 with both breast and ovarian cancer, 2 with pancreatic cancer, and 3 with no cancer but strong family history. Among the 24 patients tested, none had pathogenic BRCA1/2 mutations. However, one (4%) had a pathogenic PALB2 mutation (c.757_758del (p.Leu253Ilefs*3)), fourteen (58%) had one or more variants of uncertain significance (ALK, ATM, BARD1, BRCA2, CDKN1B, EGFR, KIT, MSH2, MSH6, MUTYH, NF1, NTHL1, POLE, RAD51D, RECQL4, SDHA, SDHB, SMARCA4, SMARCB1, TSC1), and nine (38%) had negative results. As cancer genetics becomes more mainstream, use of multigene panels has been increasing, and cost of testing has been decreasing, making this more accessible to the average Filipino cancer patient. This is the first study to document the presence of other high-penetrance breast and/or ovarian cancer susceptibility genes in Filipinos. However, more research has to be done as we still do not know all the genes that may cause hereditary breast cancer and use of multigene panels increases the rates of detecting variants of uncertain significance and other incidental findings.

Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine.

This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

“Decoding hereditary breast cancer” benefits and questions from multigene panel testing

Multigene panel testing for breast and ovarian cancer predisposition diagnosis is a useful tool as it makes possible to sequence a considerable number of genes in a large number of individuals. More than 200 different multigene panels in which the two major BRCA1 and BRCA2 breast cancer predisposing genes are included are proposed by public or commercial laboratories. We review the clinical validity and clinical utility of the 26 genes most oftenly included in these panels. Because clinical validity and utility are not established for all genes and due to the heterogeneity of tumour risk levels, there is a substantial difficulty in the routine use of multigene panels if management guidelines and recommendations for testing relatives are not previously defined for each gene. Besides, the classification of variant of unknown significance (VUS) is a particular limitation and challenge. Efforts to classify VUSs and also to identify factors that modify cancer risks are now needed to produce personalised risk estimates. The complexity of information, the capacity to come back to patients when VUS are re-classified as pathogenic, and the expected large increase in the number of individuals to be tested especially when the aim of multigene panel testing is not only prevention but also treatment are challenging both for physicians and patients. Quality of tests, interpretation of results, information and accompaniment of patients must be at the heart of the guidelines of multigene panel testing.

Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group.

To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances.

Meckel–Gruber syndrome (MKS) is a lethal autosomal recessive congenital anomaly syndrome caused by mutations in genes encoding proteins that are structural or functional components of the primary cilium. Conditions that are caused by mutations in ciliary genes are collectively termed the ciliopathies, and MKS represents the most severe condition in this group of disorders. The primary cilium is a microtubule-based organelle, projecting from the apical surface of vertebrate cells. It acts as an “antenna” that receives and transduces chemosensory and mechanosensory signals, but also regulates diverse signaling pathways, such as Wnt and Shh, that have important roles during embryonic development. Most MKS proteins localize to a distinct ciliary compartment called the transition zone (TZ) that regulates the trafficking of cargo proteins or lipids. In this review, we provide an up-to-date summary of MKS clinical features, molecular genetics, and clinical diagnosis. MKS has a highly variable phenotype, extreme genetic heterogeneity, and displays allelism with other related ciliopathies such as Joubert syndrome, presenting significant challenges to diagnosis. Recent advances in genetic technology, with the widespread use of multi-gene panels for molecular testing, have significantly improved diagnosis, genetic counseling, and the clinical management of MKS families. These include the description of some limited genotype–phenotype correlations. We discuss recent insights into the molecular basis of disease in MKS, since the functions of some of the relevant ciliary proteins have now been determined. A common molecular etiology appears to be disruption of ciliary TZ structure and function, affecting essential developmental signaling and the regulation of secondary messengers.

Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know.

This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options. The use of multigene panels, using next-generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available.

Advances in renal genetic diagnosis.

Most genetic disorders are clinically and genetically heterogeneous. Next-generation sequencing (NGS) has revolutionized the field and is providing rapidly growing insights into the pathomechanism of hereditary nephropathies. Current best-practice guidelines for most hereditary nephropathies include genetic diagnostics. The increasing number of genes that have to be considered in patients with hereditary nephropathies is often challenging when addressed by conventional techniques and largely benefits from NGS-based approaches that allow the parallel analysis of all disease genes in a single test at relatively low cost, e.g., by the use of multi-gene panels. Knowledge of the underlying genotype is of advantage in discussions with regard to transplantation and therapeutic options. Further, genetics may aid the early detection and treatment of renal and extrarenal complications and the reduction of invasive procedures. An accurate genetic diagnosis is crucial for genetic counselling, provides information about the recurrence risk and may help to improve the clinical management of patients and their families. The bottleneck in genetics is no longer the primary wet lab process but the interpretation of the obtained genetic data, which is by far the most challenging and work-intensive part of the analysis. This can only be managed in a multidisciplinary setting that brings together expert knowledge in genetics and the respective medical field. In the future, bench and bedside benefits can be expected from this kind of digitized medicine.

Patterns of genetic screening for hereditary cancer syndromes: Effect of Supreme Court’s ruling invalidating single gene patent rights.

1580 Background: In 6/2013 the Supreme Court ruled that isolated DNA sequences found in nature could not be patented, resulting in rapid uptake of multigene panels. We sought to explore trends in genetic testing since this ruling. Methods: Results of all patients undergoing genetic testing and counseling at a single institution between 7/1/13 and 12/31/16 were reviewed. Associations between categorical variables were evaluated by chi-square tests or Fisher's exact tests as appropriate for category size. Results: 1663 patients underwent genetic testing over the study period. The median age was 49 years (range 18-86). Use of multigene panels versus targeted gene testing increased significantly in the years following the Supreme Court ruling (Table 1, P&lt;0.001). While the percentage of patients found to have pathogenic mutations remained stable over the study period (9%), detection of variants of uncertain significance (VUS) increased significantly (Table 1, P&lt;0.001). In 2013 BRCA1/2 mutations accounted for 91% of identified mutations; however this number decreased over time (2014-83%, 2015-70%, 2016-58%, P=0.01). Use of multigene panels detected 71% of mutations in non- BRCA1/2 genes such as CHEK(19), APC(44), MSH6(1), P53(1), and PTEN(1). Patients with a personal history of breast and/or ovarian cancer were more likely to have targeted testing than patients with other cancer types (590, 66% vs. 9, 33%, P=0.001). Conclusions: The uptake of multigene panels has increased since the 2013 Supreme Court ruling. While this technology allowed for the identification of many cancer-related genes that would be missed on targeted BRCA1/2 testing, it also resulted in a significantly increased detection of VUS, a finding with unknown clinical implications. [Table: see text]