Indications For Genetic Testing Research Articles

Genetic Counseling, Testing, and Family Communication Into Survivorship After Diagnosis of Breast Cancer.

To examine receipt of genetic testing and communication with relatives about results into survivorship after diagnosis of breast cancer. Women age 20-79 years diagnosed with early-stage breast cancer in 2014-2015 and reported to the Georgia and Los Angeles County SEER registries were surveyed approximately 7 months and 6 years after diagnosis (n = 1,412). We asked about genetic counseling, testing, and communication with relatives about results. We categorized women into indications for testing on the basis of clinical guidelines at the time of diagnosis and at the time of the follow-up survey (FUPs). A total of 47.4% had indications for genetic testing at any time: 28.0% at baseline and an additional 19.4% at the time of the FUPs (only); 71.9% (95% CI, 67.4 to 76.4) of those with a baseline indication reported genetic testing versus 53.3% (95% CI, 47.3 to 59.2) with an indication at FUPs only and 35.0% (95% CI, 31.6 to 38.4) with no indication (P < .001). There were no significant racial or ethnic differences in receipt of testing, controlling for age and clinical indications (P = .239); results for genetic counseling were similar. Only 3.4% of survivors had direct-to-consumer genetic testing (DTCt) for cancer. Testers who reported a pathogenic variant (n = 62) were much more likely to have talked to most or all their first-degree adult relatives about genetic testing than those with a variant of unknown significance (n = 49) or a negative finding (n = 419): 62.7% versus 38.8% and 38.0%, respectively (P < .001). Many women with indications for genetic counseling and testing into survivorship do not receive it. But those tested reach out to family members on the basis of the clinical relevance of their results. Very few patients obtained DTCt, which suggests that these tests do not substitute for clinical testing in breast cancer survivors.

#2316 Towards the new era of nephrology. What implications do genetic studies have on individuals with kidney disease?

Abstract Background and Aims The study of kidney disease (KD), including genetics, may involve a significant change in the management, treatment, and prognosis of the patient. Method Retrospective study assessing the impact of genetic studies (GS) requested by the nephrology department at Virgen Macarena Hospital over 43 months (June/2019 to December/2022). We analyze diagnoses before and after GS, as well as their impact. The sequencing platforms used include Illumina HiSeq-MiSeq-NovaSeq and Ion Torrent. Common databases consulted include ClinVar, RefSeq, Ensembl, NCBI, ExAC, aHUS, and BIER. Results A total of 118 patients with genetic studies (GS) were analyzed. The mean age was 45.2 ± 16, with 51% being male and 49% female. 78% had first and/or second-degree relatives with kidney disease, and in 43 cases (36%), no family history was known. The mean creatinine (Cr) was 1.9±2 mg/dl, glomerular filtration rate (GFR) was 67 ± 40 ml/min, and urine albumin/creatinine ratio (UAC) was 770 ± 1700 mg/g, with hematuria present in 57.6% of patients. A renal biopsy (RB) was performed in 32 patients (27%). The indications for genetic testing were as follows: extension of studies in biopsied nephropathy (20%), cystic kidney disease (29%), non-biopsiable or chronic kidney disease (21%), family history (33%), and for research or trial purposes (1%). In 22%, a study of a known familial mutation was conducted, while the remaining cases involved gene panel analysis. The pre-genetic diagnoses were as follows: 39% glomerular disease, 22% other conditions (suspected Alport and Fabry), 16% autosomal dominant polycystic kidney disease (ADPKD), 8% complement-associated pathology (CAP), 5% other cystic diseases, 4% tubulointerstitial nephropathies (TIN), 3% nephropathy of unknown origin, 2% diabetic nephropathy, and 2% nephroangiosclerosis. GS was positive in 76 patients (N = 76; 64%). Variants were detected in 76 patients, with 14 patients exhibiting two concurrent variants in the same or different genes, and 4 patients having up to 3 variants. The most frequent variants were identified in the genes: COL4A, PKD1, C3, MCP, and CFH. Of these, 37% were pathogenic mutations, 26.6% were likely pathogenic, 33% were variants of uncertain significance (VUS) possibly related to the pathology, and 3.2% were unrelated VUS. In cases with negative GS results (42; 35%), we considered that the pre-genetic diagnosis was excluded in 17% of the overall patient cohort. Post-GS diagnoses included Alport (30; 25%), ADPKD (16, 14%), CAP (13; 11%), focal segmental glomerulosclerosis (6; 5%), TIN (4; 3%), autosomal recessive polycystic kidney disease (ARPKD) (1; 1%), congenital anomalies of the kidney and urinary tract (CAKUT) (1; 1%), and other conditions (5; 4%). The concordance between the pre-genetic diagnosis and GS result was 52% (N = 61). It led to a change in diagnosis in 48% of patients (N = 56); both positive and exclusionary results had an impact on clinical management in 83% (N = 98), and it resulted in a change in treatment in 20% (N = 24). Conclusion Genetic studies allow us to trace the origin of the kidney disease, providing a fundamental diagnostic tool. According to the literature, the most frequently diagnosed variants were those related to Alport syndrome, renal polycystic disease (with PKD1 being the most common), and mutations associated with complement pathway pathology. The implications and diagnostic changes brought about by genetic studies justify their implementation. In some cases, they also reclassify the kidney disease in our patients, enabling access to specific treatments.

Abstract TP280: Monogenetic Stroke Syndrome Testing in Adults: A Single Center Experience

As access and coverage of genetic testing has increased, it is being used more commonly in adults with strokes. However, no clear guidelines exist for who should undergo genetic testing. Our retrospective review aims to provide guidance in this regard and show our experience. Genetic testing was ordered at our comprehensive stroke center between June 2022 and September 2023. Tests were ordered from GeneDx and genetic material was collected by buccal swab after consent was obtained. Most of the testing was done routinely in the outpatient setting, but was rarely performed inpatient when diagnosis would change acute management. Genetic testing was ordered for 41 patients. Tests ordered included whole exome sequencing, mitochondrial genome sequencing, Marfan syndrome and thoracic aortic aneurysm and dissection panel, Disorders of connective tissues panel and expedited whole genome sequencing. Indications for testing included evaluation of carotid and vertebral dissections, recurrent stroke, cryptogenic stroke, and leukoencephalopathy. The average age of tested patients was 47. Of these patients, 6 had not had a stroke and the testing was ordered to evaluate etiology of vertebral or carotid dissections. Of the 35 patients being evaluated for stroke etiology, 60% had at least one stroke or TIA prior to presentation. Of patients tested, 14 had evidence of dissection in the carotid arteries or vertebral arteries. At the time of analysis, 27 patients had results available, of which 15 had negative results. Positive results with pathogenic variant were seen in 4 patients. Pathologic variants detected included mutations in ABCC6, NOTCH3, MT-TL1, HBB, and MCCACHC genes. Variants of unknown significance were seen in 8 patients. These variants included mutations in MYLK, COL5A1, COL5A2, KRIT1, CCM2, XPR1, MT-CYB, MT-ND4, and MT-ATP6 genes. This study highlights that in the right clinical population, like young patients with recurrent stroke, genetic testing can be helpful to elucidate the etiology of cerebrovascular disease when standard stroke work up is inconclusive. With retrospective review, we aim to provide guidance on indications for genetic testing in adults with stroke and dissection.

Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts.

The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.

Genetic testing for diffuse lung diseases in children.

Newly developing genomic technologies are an increasingly important part of clinical care and thus, it is not only important to understand the technologies and their limitations, but to also interpret the findings in an actionable fashion. Clinical geneticists and genetic counselors are now an integral part of the clinical team and are able to bridge the complexities of this rapidly changing science between the bedside clinicians and patients. This manuscript reviews the terminology, the current technology, some of the known genetic disorders that result in lung disease, and indications for genetic testing with associated caveats. Because this field is evolving quickly, we also provide links to websites that provide continuously updated information important for integrating genomic technology results into clinical decision-making.

Prenatal isolated clubfoot increases the risk for clinically significant exome sequencing results.

To examine the diagnostic yield of exome sequencing (ES) in singleton pregnancies with isolated fetal clubfoot. Clinical data from singleton pregnancies with a sonographic diagnosis of isolated clubfoot and ES results between 2018 and 2021 were retrospectively obtained from a single referral medical center. The recorded data include maternal age, gestational age at sonographic diagnosis, the indication for genetic testing, ES results, and pregnancy outcomes. During the study period, 38 fetuses were prenatally diagnosed with isolated clubfoot by ultrasound and underwent ES after the copy number variant analysis was non-diagnostic. Through the trio-ES analysis, pathogenic or likely pathogenic variants were detected in 4 of 38 (10.5%) with the following genes: BRPF1, ANKRD17, FLNA, and KIF1A. All are de novo with three of autosomal dominant inheritance and one of X-linked recessive inheritance. Sonographic diagnosis of clubfoot, even isolated, increases the risk for monogenic syndromes. Exome sequencing should be an option for genetic investigation for such pregnancies.

Genetic Testing and Its Clinical Application in Prostate Cancer Management: Consensus Statements from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology

BackgroundIn recent years, indications for genetic testing in prostate cancer (PC) have expanded from patients with a family history of prostate and/or related cancers to those with advanced castration-resistant disease, and even to early PC patients for determination of the appropriateness of active surveillance. The current consensus aims to provide guidance to urologists, oncologists and pathologists working with Asian PC patients on who and what to test for in selected populations.MethodsA joint consensus panel from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology was convened over a series of 5 physical and virtual meetings. A background literature search on genetic testing in PC was performed in PubMed, ClinicalKey, EBSCOHost, Ovid and ProQuest, and three working subgroups were formed to review and present the relevant evidence. Meeting agendas adopted a modified Delphi approach to ensure that discussions proceed in a structured, iterative and balanced manner, which was followed by an anonymous voting on candidate statements. Of 5 available answer options, a consensus statement was accepted if ≥ 75% of the panelists chose “Accept Completely” (Option A) or “Accept with Some Reservation” (Option B).ResultsThe consensus was structured into three parts: indications for testing, testing methods, and therapeutic implications. A list of 35 candidate statements were developed, of which 31 were accepted. The statements addressed questions on the application of PC genetic testing data and guidelines to Asian patients, including patient selection for germline testing, selection of gene panel and tissue sample, provision of genetic counseling, and use of novel systemic treatments in metastatic castration-resistant PC patients.ConclusionThis consensus provides guidance to urologists, oncologists and pathologists working with Asian patients on indications for genetic testing, testing methods and technical considerations, and associated therapeutic implications.

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study.

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

The role of genetic counselling in oncology

All cancers are genetic disorders, but not all genetic disorders are inherited. Most cancers are sporadic, independent events that do not affect other family members. There is a population risk of developing any cancer and it mainly depends on the individual’s age and environmental factors. Cancers linked to predisposition syndromes constitute about 5–10% of all cancer cases. Although it is a small group, making the right diagnosis is important, because of the consequences to the individual, his/her relatives and the benefits they can acquire from surveillance, early therapy and/ or surgical interventions. Genetic counselling plays an important role in diagnosing cancer predisposition syndromes. Hereditary cancer risk assessment includes evaluation of personal and family history, as well as other medical and environmental risk factors. Indications for genetic testing, scope of tests, possible results and their consequences for the patient and his/her family should be discussed.

High-risk phenotypes of genetic disease in a Neonatal Intensive Care Unit population.

High-risk phenotypes of genetic disease in a Neonatal Intensive Care Unit population.

Abstract 11337: Sensitivity Analysis of an Electronic Health Record-Based Algorithm to Facilitate Detection of Familial Hypercholesterolemia: Results in Genetically Confirmed Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder resulting in elevated LDL-C levels and increased risk of cardiovascular disease. Algorithms have been developed to facilitate FH detection. We previously developed a continuous, electronic health record (EHR)-based algorithm using the Dutch Lipid Clinical Network (DLCN) criteria, with automated correction of LDL-C levels for use of lipid-lowering-therapy (LLT). In this study, we performed a sensitivity analysis of the algorithm in patients with previously genetically confirmed FH. Methods: We selected all patients with genetically confirmed FH, seen during 2018 and 2019. DLCN scores were calculated before and after correction for LLT at the most recent visit. The primary outcome was the number of FH patients with DLCN criteria ≥6 points for LDL-C (which would have been an indication for genetic testing) before and after correction for LLT. Secondary endpoint was the additional number of patients with ≥6 points after also adding data on patient- and family history. Results: We included 222 patients with genetically confirmed FH; mean (SD) age: 50 (17) years; female: n=134 (60,4%). In total, 210 patients (94,6%) used some type of LLT. Mean (SD) LDL-C was 3,0 (1,4) mmol/L before correction for LLT and 7,5 (3,7) mmol/L after correction for LLT. Before correction for LLT, the algorithm identified 3 patients (1,4%) with ≥6 DLCN points, increasing to 59 patients (26,6%) after correction for LLT and to 76 patients (34,2%) after adding data on patient-, and family history. Conclusion: We conclude that, even after correction for LLT and addition of data on patient-, and family history, the sensitivity of a DLCN-based algorithm appeared relatively low in a population with genetically confirmed FH. Correction for LLT is important to increase sensitivity of the algorithm. Interestingly, FH detection algorithms inevitably rely on phenotypical characteristics of patients, whereas the present data show that genotypical FH does not necessarily express as phenotypical FH recognized by the DLCN-based algorithm. These data highlight the need for improvement of the DLCN-based algorithm and the importance of cascade testing for FH.

ПОЧЕЧНО-КЛЕТОЧНАЯ КАРЦИНОМА С ДЕФИЦИТОМ СУКЦИНАТДЕГИДРОГЕНАЗЫ В У РЕБЕНКА 15 ЛЕТ С СИНДРОМОМ НАСЛЕДСТВЕННОЙ ФЕОХРОМОЦИТОМЫ И ПАРАГАНГЛИОМЫ 4-го ТИПА

Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC) is histological variant of RCC recently recognized and included in the classification of renal tumors. SDH-deficient RCC constitutes only 0,02–0,5% of all RCC. The main role in the development of this malignant neoplasm (MN) belongs to mutations in the genes of succinate dehydrogenase (SDHx). The article presents a clinical case report of SDH-deficient RCC in the 15-year-old child. RCC developed as a consequence of the syndrome of hereditary pheochromocytoma and paraganglioma type 4. A literature review describes the histological and molecular genetic characteristics of SDH-deficient RCC, the clinical picture, approaches to therapy and monitoring of patients, as well as indications for genetic testing of patients and their relatives to identify cancer predisposition syndromes.

Prevalence of pathogenic mutations and variants of uncertain significance in patients undergoing hereditary cancer genetic testing in Cambridge, MA.

e22506 Background: Genetic testing allows for enhanced prognostication and early intervention in patients with high risk of developing cancer. Genetic testing often reveals variants of uncertain significance (VUS), for which association with disease risk is unclear. The ambiguity of this finding creates a dilemma for patients and providers and has been associated with significant communication error and distress. In this retrospective observational study, we seek to characterize the indications, outcomes, and trends in patients undergoing genetic testing in a community hospital in Cambridge, MA. As our study spanned the beginning of the COVID-19 pandemic, we also assessed its impact on care accessibility. Methods: We included patients undergoing genetic testing at our hospital between December 2019 and October 2020 (n=371). Medical charts were abstracted to identify patient characteristics, family history, indication for genetic testing, genetic findings, and subsequent management. Results: Our population had a mean age of 48 years (SD=15), was predominantly female (88.1%), and had a high proportion of Ashkenazi Jewish descent (15.3%). The vast majority (351, 94.6%) had a family history of cancer, while 123 (33.2%) had a personal history of cancer, most commonly breast (n=89). The most common indications for genetic testing were Hereditary Breast and Ovarian Cancer (HBOC in 280, 75%), Lynch Syndrome (LS in 22, 5.9%), and Familial Adenomatous Polyposis (FAP in 7, 2%). Of patients who met HBOC, LS, or FAP criteria for genetic testing, pathogenic mutations were identified in 9.5% and VUS in 28.6%. Out of total 35 (9.4%) pathogenic mutations found in our entire study population, the most common were in BRCA (9, 25.7%), MUTYH (5, 14.2%), and Lynch genes (3, 8.6%). Out of 103 patients with VUS (27.8%), the most common sites were APC (14) and MSH3 (9). We found no significant trend in genetic counseling consultations over our 11 months study period despite the COVID-19 pandemic (R2 = 0.006). Conclusions: Among patients who met criteria for genetic cancer screening at a community hospital, 9.5% were found to have a pathogenic mutation while 28.6% were found to have VUS. These numbers are comparable to previously published estimates. Despite advances in our understanding of genetic colon and gynecological cancers, the majority of patients presenting for genetic cancer counseling continue to do so due to breast cancer concerns. Lastly, we noted high efficacy in our conversion of in-person genetics consultations to telemedicine during the COVID-19 pandemic, suggesting telemedicine is a robust format for genetic counselling. Mutations (N): BRCA1 (3), BRCA2 (6); MUTHY (5); MSH2 (2), MSH6 (1); ATM (2), and one each in PALB2, RAD50, RAD51C, RAD51D, Tp53, CDKN2A, APC, F2, SDHA, SDHB, VHL. FANCL, NTHL1.

Impact of national guidelines on use of BRCA1/2 germline testing, risk management advice given to women with pathogenic BRCA1/2 variants and uptake of advice

BackgroundThis nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients.MethodsClinic files of 883 women who had initial proband screens for BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008–July 2009 (i.e. before guideline release), July 2010–July 2011 and July 2012–July 2013 (both after guideline release) were audited to determine reason given for genetic testing. Separately, the clinic files of 599 female carriers without a personal history of breast/ovarian cancer who underwent BRCA1/2 predictive genetic testing and received their results pre- and post-guideline were audited to ascertain the risk management advice given by health professionals. Carriers included in this audit were invited to participate in a telephone interview to assess uptake of advice, and 329 agreed to participate.ResultsThere were no significant changes in the percentages of tested patients meeting at least one published indication for genetic testing - 79, 77 and 78% of files met criteria before guideline, and two-, and four-years post-guideline, respectively (χ = 0.25, p = 0.88). Rates of documentation of post-test risk management advice as per guidelines increased significantly from pre- to post-guideline for 6/9 risk management strategies. The strategies with the highest compliance amongst carriers or awareness post-release of guidelines were annual magnetic resonance imaging plus mammography in women 30–50 years (97%) and annual mammography in women > 50 years (92%). Of women aged over 40 years, 41% had a risk-reducing bilateral mastectomy. Amongst women aged > 40 years, 75% had a risk-reducing salpingo-oophorectomy. Amongst women who had not had a risk-reducing bilateral mastectomy, only 6% took risk-reducing medication. Fear of side-effects was cited as the main reasons for not taking these medicines by 73% of women.ConclusionsGuidelines did not change the percentages of tested patients meeting genetic testing criteria but improved documentation of risk management advice by health professionals. Effective approaches to enhance compliance with guidelines are needed to improve risk management and quality of care.

Streamlining the genetics pipeline to increase testing for patients at risk for hereditary prostate cancer.

66 Background: At UCSF, ~850 men with metastatic prostate cancer are seen annually, all of whom should receive germline genetic testing. Prior to our study, the GU medical oncology program offered a self-pay, take-home genetic testing kit (30-gene panel) to patients with metastatic prostate cancer. Patients with positive test results were referred for genetic counseling. For this study, the UCSF Cancer Genetics and Prevention program partnered with the GU medical oncology program, adapting a Genetic Testing Station (GTS) to expand access and accommodate testing needs. At Prostate GTS, a genetic counselor assistant (GCA) facilitates cancer genetics education by video, enrolls patient in a research registry, collects a family history and saliva sample sent for an 87-gene panel. Our study evaluates the effectiveness of the GTS by comparing prospective performance metrics and testing outcomes of Prostate GTS with retrospective data obtained from the take-home method (“Before GTS”). Methods: Men were ascertained by their treating oncologist and referred for GTS. Indications for genetic testing include: all metastatic prostate cancer, or under age 50 at diagnosis, or with family history, or at clinician discretion. GTS metrics were prospectively collected by clinical staff. “Before GTS” metrics were retrospectively collected through data reporting from commercial lab analysis (test orders dated 01/2017 to 09/2019) and patient chart review. Results: In the first 6 months of Prostate GTS (10/2019-3/2020), 139 patients received testing at the GTS and 91% (127) had received results at censoring. GTS results were distributed as follows: 10% (13) positives, 33% (42) negative no VUS, and 57% (72) negative w/VUS. In the 33 months, “Before GTS”, 218 genetic testing orders had been placed, with 78% (196) reported at censoring, distributed as 11% (22) positive, 68% (134) negative no VUS, and 20% (40) negative w/VUS. The rate of incomplete tests decreased significantly with the GTS, (22% down to 9%, p = 0.0008). "Before GTS", of patients with a positive result, 15/22 (68%) were referred for genetic counseling, of which 8 completed a visit (36% of all positives). In the GTS model, all patients with positive results were seen by a genetic counselor for results disclosure and counseling. Comparing result rates across similar timeframes, 127 results were reported from GTS compared to 40 results from “Before GTS” in the same calendar months the year prior, representing a 218% increase in returned results. Median turnaround time decreased from 16 days to 9 days with GTS. Conclusions: GTS efficiently increased access to genetic testing and counseling for patients with prostate cancer. By leveraging GCAs and video education, this model involves cancer genetics at each step of the process, decreases turnaround time, and increases rates of returned results that can be used by patients to inform treatment and prevention strategies.

Abstract PS8-24: Clinical and pathologic characteristics of Turkish breast cancer (BC) patients screened with BRCA1, BRCA2 or 26 - gene inherited cancer panel testing: Single institution experience

Abstract Background: BRCA1 and BRCA2 mutations are responsible for two thirds of hereditary BC. Germline genetic testing for BC susceptibility has evolved from a single-gene analysis to a multigene panel testing. Identification of a pathogenic mutation in BRCA and other panel represent a therapeutic opportunity today. Methods: We aimed to investigate clinical and pathologic characteristics of BC patients who were referred to our center between 2011-2019 and underwent BRCA1, BRCA2 or 26-gene inherited cancer panel testing based on NCCN criteria for hereditary breast/ovarian cancer testing. We analyzed the frequency of pathogenic mutations and its relationship with clinical and pathologic factors. Results: A total of 576 patients were identified. Among them 356 (63%) had their test in our university, 218 (38%) patients had their test at other centers. Sixty-six % (n:376) of patients had panel testing, 34% had only BRCA 1-2 mutation test. Median age was 42(22-87) and 5 patients were male. Ten % of patients had metastatic disease, 70% had early BC and 20% had locally advanced stage at the time of referral. The indication for genetic testing was family history in 169 (29%) patients, triple negative (TN) subtype in 100 (17%) patients and age &amp;lt;45 years in 260 (45%) patients. Seventy-nine % of patients were premenopausal. A total of 114 (19%) patients had pathogenic mutations. The most commonly mutated genes were BRCA1 (n:38, 6%), BRCA2 (n:35, 6%), ATM (n:6), p53 (n:5), PALB2 (n:5), CHEK2 (n:5). Six patients had more than one pathogenic mutation. Among patients with pathogenic mutations 58% had ER positive, 27% had TN and 15 % had Her-2 positive disease. Thirty-four % of patients with TN tumors have pathogenic mutations, 23% of patients with TN tumors had BRCA mutations. TP53, PALB2 and CHEK2 mutations were more frequent in HR positive disease. Age &amp;lt;35 (p:0.002), triple negative subtype (p: 0.005) and menopausal status (p:0.001) were significantly associated with having pathogenic mutations in multivariate analysis. Conclusion: Two thirds of BC patients &amp;lt;35 years-old and one third of patients with TN tumors have pathogenic germline mutations in BC predisposing genes when they were screened in line with NCCN criteria. Citation Format: Aysun Isiklar, Aykut Soyder, Kanay Yararbas, Cumhur Ekmekci, Hulya Yazici, Gul Basaran. Clinical and pathologic characteristics of Turkish breast cancer (BC) patients screened with BRCA1, BRCA2 or 26 - gene inherited cancer panel testing: Single institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-24.

Access to breast/ovarian genetic testing: 20 years of a multidisciplinary program.

e14015 Background: After institutional and ethical review, a multidisciplinary Breast/Ovarian Cancer Family Risk program started in January 2000. Core team included medical oncologists, molecular biologists, medical geneticists and specialized nurses. Besides access to genetic testing (GT), predictive risk analysis and tailored surveillance plans were provided for women without criteria for GT, and carriers of germline pathogenic/likely pathogenic variants (PV/LPV) were included in prospective follow up. Methods: Descriptive statistics concerning patients (pts), medical visits and genetic tests performed under the program from January 2000-December 2019. Results:A total of 28400 medical appointments (including multidisciplinary meetings with radiology, breast and plastic surgery and gynecology) were performed for 10100 pts: 9281 women (92%) and 819 men (8%), with an average of 46,0 years (45,6 and 51,1 respectively). Most pts were referred from our cancer center or were invited for cascade testing (8044, 79,6%), although we accepted referrals from external health services (2056 pts). GT: 5665 tests performed (4454 for index pts (IP) and 1211 for family relatives); 3170 (71%) IP consented only in BRCA1/2 and 1284 IP (29%) in sequential/panel testing. Detection rate for IP testing was 12,5% [440 BRCA1/2; 118 Other Hereditary Syndromes (OSH)]. OHS IP: CHEK2(32), ATM(14), TP53(11), MUTYH(12), PALB2(10), RAD51D(10), RAD51C(9), BLM(5), BRIP1(4), RAD50 (4), PTEN(2), MSH2(2), MLH1(1) FAM175A(1), BARD1(1). Six- hundred and twenty-six IP with previous inconclusive results consented on panel testing and 62(9,9%) were diagnosed with a non- BRCA1/2 PV/LPV. Until June 2019, 915 BRCA1/2 pts were included in a registry for prospective follow up. Conclusions: our program has allowed for access to Breast/Ovarian GT and risk management in the National Health Service, for the past 20 years. Twenty per cent of all pts are referrals from external health services. The ever increasing challenges to the resources of the program include: new indications for GT, the increase in priority pts for GT due to more therapy options, risk dynamics in previous registered families, evolving molecular methodologies and the management of families with complex genetic variants. The growing number of pts, including men, led to a recent change in the label of the program (Breast/Ovarian/Prostate Cancer Family Risk) and new approaches to promote access of specific populations to GT (like telegenetics) are being tested.

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family

BackgroundHereditary diffuse gastric cancer is a rare condition that accounts for approximately 1–3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer.Case presentationA 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient’s young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient’s father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy.ConclusionAwareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.

Prevalence of genetically verified familial hypercholesterolemia among young (

Patients with familial hypercholesterolemia (FH) have an increased risk of premature myocardial infarction (MI). The objective of the study is to investigate the prevalence of FH among young patients hospitalized with acute MI. Data were collected from medical charts of all patients aged <45years admitted with acute MI to the Department of Cardiology, Oslo University Hospital Ullevål, in the period 2012 to 2016. Patients who had not already been genetically tested for FH were contacted and offered genetic testing if the pretreatment or the statin-adjusted low-density lipoprotein cholesterol level was >4.0mmol/L (155mg/dL). Of 9332 patients admitted with acute MI, 357 were aged <45years. Sixteen patients were deceased, and 13 patients did not have MI on an atherosclerotic basis. Of the remaining 328 patients eligible for investigation, 130 had the pretreatment or statin-adjusted low-density lipoprotein cholesterol level >4.0mmol/L (155mg/dL). Of these, data from 52 patients genetically tested for FH were available. Eleven patients had genetically verified FH constituting 3.4% of the total eligible population (n=328), 8.5% of those with indications for genetic testing (n=130), and 21.2% of those actually tested (n=52). A Dutch Lipid Clinic Network score for clinical FH diagnosis of "definite FH" identified only 5 of the 11 patients with positive genetic test (45%). Including a score of "probable FH" identified all patients with FH but also 17 of the 41 patients (41%) with a negative genetic test. The prevalence of FH in young patients with acute MI was higher than in the general population. Routine evaluation of FH diagnosis among these patients could identify more patients with FH, thereby increasing the possibility of initiating early and adequate treatment also among affected relatives.

Genetic Testing in Pediatric Kidney Disease.

The advent of next gene sequencing technology has led to the publication of a profusion of papers on monogenic contributions to pediatric kidney disorders. It started with the discovery of mutations in the podocin gene in steroid resistant nephrotic syndrome (SRNS). It is realized now that genetic disorders contribute to about 30% of chronic renal diseases in children, and significantly to many other kidney disorders. This paper covers briefly the new genetic technologies, the benefits of genetic testing, and the indication for genetic testing in various kidney disorders. It covers SRNS, congenital anomalies of the kidney, cystic kidney disease, tubulopathies, nephronophthisis, Fabry disease, Alport and Lowe syndrome. Atypical hemolytic uremic syndrome, renal tubular acidosis and nephrolithiasis are also covered briefly. It is hoped that this paper will encourage the pediatricians to investigate monogenic disorders of the kidney as it helps in their proper classification, informs prognosis, suggests specific treatment and aids in genetic and reproductive counseling.