scholarly journals New Case Detection by Cascade Testing in Familial Hypercholesterolemia

2019 ◽  
Vol 12 (11) ◽  
Author(s):  
Christopher Lee ◽  
Miriannie Rivera-Valerio ◽  
Hana Bangash ◽  
Larry Prokop ◽  
Iftikhar J. Kullo
Keyword(s):  
Genetic Testing ◽  
Familial Hypercholesterolemia ◽  
Direct Contact ◽  
Index Case ◽  
The United States ◽  
Case Detection ◽  
Sample Collection ◽  
Cascade Testing ◽  
First Degree Relatives ◽  
The Mean

Background: The prevalence of familial hypercholesterolemia is 1 in 250, but <10% of patients are diagnosed. Cascade testing enables early detection of cases through systematic family tracing. Establishment of familial hypercholesterolemia cascade testing programs in the US could be informed by approaches used elsewhere. Methods: We conducted a systematic review of published studies in the English language of cascade testing for familial hypercholesterolemia, which reported the number of index cases and number of relatives tested and specified methods of contacting relatives and testing modalities methods utilized. For each study, we calculated yield (proportion of relatives who test positive) and new cases per index case, to facilitate comparison. Results: We identified 10 studies from the literature that met inclusion criteria; the mean number of probands and relatives per study was 242 and 826, respectively. The average yield was 44.76% with a range of 30% to 60.5%, and the mean new cases per index case was 1.65 with a range of 0.22 to 8.0. New cases per index case tended to be greater in studies that used direct contact versus indirect contact (2.06 versus 0.86), tested beyond first-degree relatives versus only first-degree relatives (3.65 versus 0.80), used active sample collection versus collection at clinic (4.11 versus 1.06), and utilized genetic testing versus biochemical testing (2.47 versus 0.42). Conclusions: New case detection in familial hypercholesterolemia cascade testing programs tended to be higher with direct contact of relatives, testing beyond first-degree relatives, in-home–based sample collection, and genetic testing. These findings should be helpful for establishing cascade testing programs in the United States.

scholarly journals Compound Heterozygous Familial Hypercholesterolemia and Familial Defective Apolipoprotein B-100 Produce Exaggerated Hypercholesterolemia

2001 ◽  
Vol 47 (3) ◽  
pp. 438-443 ◽  
Author(s):  
E Shyong Tai ◽  
Evelyn S C Koay ◽  
Edmund Chan ◽  
Tzer Jing Seng ◽  
Lih Ming Loh ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Genetic Analysis ◽  
Familial Hypercholesterolemia ◽  
Apolipoprotein B ◽  
Ldl Cholesterol ◽  
Index Case ◽  
Ldl Receptor ◽  
Cholesterol Concentration ◽  
Apo B ◽  
First Degree Relatives

Abstract Background: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) represent ligand-receptor disorders that are complementary. Individuals with both FH and FDB are unusual. We report a family with both disorders and the impact of the mutations on the phenotypes of the family members. Methods: We used single strand conformation polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) for genetic analysis of all 18 exons and the promoter region of the LDL receptor and DGGE for genetic analysis of the apolipoprotein B-100 (apo B-100) gene. The functional significance of the apo B-100 mutation was studied using a U937 cell proliferation assay. Fasting serum lipid profiles were determined for the index case and seven first-degree relatives. Results: One of the patient’s sisters had a missense mutation (Asp407→Lys) in exon 9 of the LDL receptor and a serum LDL-cholesterol concentration of 4.07 mmol/L. Four other first-degree relatives had hyperlipidemia but no LDL-receptor mutation. However, these subjects had a mutation of the apo B-100 gene (Arg3500→Trp). The cell proliferation rate of U937 cells fed with LDL from other subjects with the same mutation was fourfold less than that of controls. The index case had both FH- and FDB-related mutations. Her serum LDL-cholesterol (9.47 mmol/L) was higher than all other relatives tested. Conclusions: Existence of both FH and FDB should be considered in families with LDL-receptor mutations in some but not all individuals with hypercholesterolemia or when some individuals in families with FH exhibit exaggerated hypercholesterolemia.

Facilitated cascade testing (FaCT): a randomized controlled trial

2020 ◽  
pp. ijgc-2020-002118
Author(s):  
Roni Nitecki ◽  
Haley A Moss ◽  
Catherine H Watson ◽  
Diana L Urbauer ◽  
Alexander Melamed ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Controlled Trial ◽  
Randomized Study ◽  
Standard Of Care ◽  
Pathogenic Mutation ◽  
Primary Objective ◽  
Care Group ◽  
Patient Navigator ◽  
Cascade Testing ◽  
First Degree Relatives

BackgroundIdentifying mutation-carrying relatives of patients with hereditary cancer syndromes via cascade testing is an underused first step in primary cancer prevention. A feasibility study of facilitated genetic testing of at-risk relatives of patients with a known pathogenic mutation demonstrated encouraging uptake of cascade testing.Primary objectiveOur primary objective is to compare the proportion of genetic testing of identified first-degree relatives of probands with a confirmed BRCA1/2 mutation randomized to a facilitated cascade testing strategy versus standard of care, proband-mediated, information sharing.Study hypothesisWe hypothesize that facilitated cascade testing will drive significantly higher uptake of genetic testing than the standard of care.Trial designThe FaCT (Facilitated Cascade Testing) trial is a prospective multi-institutional randomized study comparing the efficacy of a multicomponent facilitated cascade testing intervention with the standard of care. Patients with a known BRCA1/2 mutation (probands) cared for at participating sites will be randomized. Probands randomized to the standard of care group will be instructed to share a family letter with their first-degree relatives and encourage them to complete genetic testing. First-degree relatives of probands randomized to the intervention arm will receive engagement strategies with a patient navigator, an educational video, and accessible genetic testing services.Major inclusion/exclusion criteriaAdult participants who are first-degree relatives of a patient with a BRCA1/2 mutation and have not had prior genetic testing will be included.Primary endpointAnalyses will assess the proportion of first-degree relatives identified by the proband who complete genetic testing by 6 months in the intervention arm versus the control arm.Sample sizeOne hundred and fifty probands with a BRCA1/2 mutation will be randomized. Each proband is expected to provide an average of 3 relatives, for an expected 450 participants.Estimated dates for completing accrual and presenting resultsJanuary 2024.Trial registrationNCT04613440

scholarly journals A Global Review on the Utility of Genetic Testing for Familial Hypercholesterolemia

2020 ◽  
Vol 10 (2) ◽  
pp. 23 ◽  
Author(s):  
Rachele M. Hendricks-Sturrup ◽  
Jodi Clark-LoCascio ◽  
Christine Y. Lu
Keyword(s):  
United States ◽  
Genetic Testing ◽  
Familial Hypercholesterolemia ◽  
Clinical Outcomes ◽  
Ldl Cholesterol ◽  
The United States ◽  
Global Perspective ◽  
Ongoing Research ◽  
Increased Risk ◽  
Patient Reported

Familial hypercholesterolemia (FH) is a genetic disorder of cholesterol metabolism that affects an estimated 1/250 persons in the United States and abroad. FH is hallmarked by high low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. This review summarizes recent global evidence showing the utility of FH genetic testing across diverse populations. Clinical and other qualitative outcomes following FH genetic testing were improved FH diagnosis, treatment initiation or continued treatment, treatment modification, improved total or LDL cholesterol levels, education on lifestyle management, and genetic counseling. This summary of evidence should be considered by those seeking overall evidence and knowledge gaps on the utility of FH genetic testing from a global perspective and for certain ethnic and age populations. These findings can be used to inform insurance policies and coverage decisions for FH genetic testing, policy recommendations to reduce the clinical and public health burden of FH, clinical practice and guidelines to improve the management of FH populations, and ongoing research involving FH genetic testing. We conclude that further investigations are needed to examine: (1) non-clinical outcomes following FH genetic testing; (2) patient-reported outcomes following FH genetic testing to convey patient experiences, values, and goals; and (3) clinical outcomes following FH genetic testing in non-Caucasian and pediatric populations in the United States and abroad.

scholarly journals Understanding Implementation Challenges to Genetic Testing for Familial Hypercholesterolemia in the United States

2019 ◽  
Vol 9 (1) ◽  
pp. 9 ◽  
Author(s):  
Rachele Hendricks-Sturrup ◽  
Christine Lu
Keyword(s):  
United States ◽  
Genetic Testing ◽  
Familial Hypercholesterolemia ◽  
Ethnic Diversity ◽  
Heart Association ◽  
The United States ◽  
Cvd Risk ◽  
Implementation Challenges ◽  
The Us ◽  
Control And Prevention

Cardiovascular disease (CVD) is the leading cause of death in the United States (US), with familial hypercholesterolemia (FH) being a major inherited and genetic risk factor for premature CVD and atherosclerosis. Genetic testing has helped patients and providers confirm the presence of known pathogenic and likely pathogenic variations in FH-associated genes. Key organizations, such as the Centers for Disease Control and Prevention (CDC), American Heart Association (AHA), FH Foundation, and National Lipid Association (NLA), have recognized the clinical utility of FH genetic testing. However, FH genetic testing is underutilized in clinical practice in the US for reasons that are underexplored through the lens of implementation science. In this commentary, we discuss seven key implementation challenges that must be overcome to strengthen the clinical adoption of FH genetic testing in the US. These implementation challenges center on evidence of cost-effectiveness, navigating patient and provider preferences and concerns, gender and ethnic diversity and representation in genetic testing, and establishing clinical consensus around FH genetic testing based on the latest and most relevant research findings. Overcoming these implementation challenges is imperative to the mission of reducing CVD risk in the US.

scholarly journals Developing and Optimizing Innovative Tools to Address Familial Hypercholesterolemia Underdiagnosis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Gemme Campbell-Salome ◽  
Laney K. Jones ◽  
Max F. Masnick ◽  
Nephi A. Walton ◽  
Catherine D. Ahmed ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Family Communication ◽  
Design Thinking ◽  
Genetic Disorder ◽  
Pragmatic Trial ◽  
The United States ◽  
Atherosclerotic Cardiovascular Disease ◽  
Patient Centered ◽  
Cascade Testing ◽  
Increased Risk

Background: Familial hypercholesterolemia (FH) is the most common cardiovascular genetic disorder and, if left untreated, is associated with increased risk of premature atherosclerotic cardiovascular disease, the leading cause of preventable death in the United States. Although FH is common, fatal, and treatable, it is underdiagnosed and undertreated due to a lack of systematic methods to identify individuals with FH and limited uptake of cascade testing. Methods and Results: This mixed-method, multi-stage study will optimize, test, and implement innovative approaches for both FH identification and cascade testing in 3 aims. To improve identification of individuals with FH, in Aim 1, we will compare and refine automated phenotype-based and genomic approaches to identify individuals likely to have FH. To improve cascade testing uptake for at-risk individuals, in Aim 2, we will use a patient-centered design thinking process to optimize and develop novel, active family communication methods. Using a prospective, observational pragmatic trial, we will assess uptake and effectiveness of each family communication method on cascade testing. Guided by an implementation science framework, in Aim 3, we will develop a comprehensive guide to identify individuals with FH. Using the Conceptual Model for Implementation Research, we will evaluate implementation outcomes including feasibility, acceptability, and perceived sustainability as well as health outcomes related to the optimized methods and tools developed in Aims 1 and 2. Conclusions: Data generated from this study will address barriers and gaps in care related to underdiagnosis of FH by developing and optimizing tools to improve FH identification and cascade testing.

scholarly journals Prospective Feasibility Trial of a Novel Strategy of Facilitated Cascade Genetic Testing Using Telephone Counseling

2020 ◽  
Vol 38 (13) ◽  
pp. 1389-1397 ◽  
Author(s):  
Melissa K. Frey ◽  
Ryan M. Kahn ◽  
Eloise Chapman-Davis ◽  
Francesca Tubito ◽  
Maira Pires ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Genetic Testing ◽  
The United States ◽  
Telephone Counseling ◽  
Pathogenic Variant ◽  
Cancer Surveillance ◽  
Feasibility Trial ◽  
Cascade Testing ◽  
Pathogenic Variants ◽  
Testing Uptake

PURPOSE A powerful consequence of detecting cancer-associated pathogenic variants is the ability to test at-risk relatives (ARRs), termed cascade testing. However, historical studies suggest cascade testing uptake of 30% or less. Here, we tested the feasibility of a novel, streamlined method of cascade testing using telephone genetic counseling and mailed saliva-based genetic testing. PATIENTS AND METHODS Probands with newly diagnosed cancer-associated pathogenic variants were offered facilitated cascade testing whereby the genetics team identified and contacted ARRs by telephone to disclose the familial pathogenic variant and offer telephone counseling and mailed saliva testing. Results and guideline-based recommendations were reviewed by telephone and shared with the primary care physician. RESULTS Thirty probands were enrolled, and 114 ARRs were identified. Twelve ARRs were excluded (lived outside of the United States, n = 5; proband did not approve of contact, n = 7). Among 102 ARRs telephoned, contact was established with 95 (93%). Among 114 identified ARRs, 66 (58%) completed genetic testing. Among those completing testing, 27 (41%) carried the familial pathogenic variant. Surveys of ARRs at the time of genetic testing and 6 months later demonstrated low levels of anxiety, depression, distress, and uncertainty and high levels of satisfaction with testing. At 6 months, 7 ARRs with pathogenic variants had undergone cancer surveillance interventions and 4 had undergone cancer risk-reducing surgery. CONCLUSION Facilitated cascade testing with telephone genetic counseling and mailed saliva kits resulted in high testing uptake among ARRs. Positive genetic testing resulted in utilization of genetically targeted primary disease prevention at short-term follow-up. Facilitated cascade testing is a straightforward, low-cost, easily implemented strategy with significant potential to promote early detection for affected ARRs and reduce cancer mortality and should be evaluated in larger scale clinical trials.

scholarly journals Barriers and Facilitators to Genetic Testing for Familial Hypercholesterolemia in the United States: A Review

2019 ◽  
Vol 9 (3) ◽  
pp. 32 ◽  
Author(s):  
Rachele M. Hendricks-Sturrup ◽  
Kathleen M. Mazor ◽  
Amy C. Sturm ◽  
Christine Y. Lu
Keyword(s):  
United States ◽  
Genetic Testing ◽  
Familial Hypercholesterolemia ◽  
Systematic Approach ◽  
The United States ◽  
Barriers And Facilitators ◽  
Clinical Settings ◽  
Vascular Events ◽  
Potential Barriers ◽  
The Us

Familial Hypercholesterolemia (FH) is an underdiagnosed condition in the United States (US) and globally, affecting an estimated 1/250 individuals. It is a genetic risk factor for premature cardiovascular disease and is responsible for an estimated 600,000 to 1.2 million preventable vascular events. Studies show that FH genetic testing can identify a causal gene variant in 60 to 80% of clinically suspected FH cases. However, FH genetic testing is currently underutilized in clinical settings in the US despite clinical recommendations and evidence supporting its use. Reasons for underutilization are not well understood. We conducted a literature review in the PubMed/MEDLINE database and eight peer-reviewed journals. After filtering for and reviewing 2340 articles against our inclusion criteria, we included nine commentaries or expert opinions and eight empirical studies reported between January 2014 and March 2019 in our review. After applying the Consolidated Framework for Implementation Research (CFIR), we identified a total of 26 potential barriers and 15 potential facilitators (estimated barrier to facilitator ratio of 1.73). We further estimated ratios of potential barriers to facilitators for each CFIR domain (Characteristics of Intervention, Outer Setting, Inner Setting, Characteristics of Individuals, and Process). Findings derived from our systematic approach to the literature and calculations of estimated baseline ratios of barriers and facilitators can guide future research to understand FH genetic testing implementation in diverse clinical settings. Our systematic approach to the CFIR could also be used as a model to understand or compare barriers and facilitators to other evidence-based genetic testing processes in health care settings in the US and abroad.

Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 143-143
Author(s):  
Rachel Sabol ◽  
Elisa Marie Ledet ◽  
Ellen Jaeger ◽  
Marcus W. Moses ◽  
Brian E. Lewis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Personal History ◽  
Sample Collection ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
Damage Repair ◽  
History Of

143 Background: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history records are incomplete in published studies. Methods: Prospective and complete family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes (Invitae testing) from 2016-2020. Comprehensive FH were obtained in all PCa patients in this database and analysis of prevalent FH was assessed at the time of sample collection. Age, race, metastastes at any time, and Gleason score were also ascertained. MUTYH heterozygotes were not considered pathogenic. Results: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. Men with Gleason scores 8-10 at time of diagnosis were more likely to have PV/LPV ( P= 0.004). One or more first degree relatives (FDR) with any cancer with was not predictive for germline PV/LPVs for men with PCa ( P= 0.96). Analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast cancer ( P = 0.028) or ovarian cancer ( P = 0.015) was predictive for PV/LPVs. Though one or more FDR with prostate cancer did not predict a PV/LPV in the overall panel, further analysis indicate that a history of a FDR with PCa was predictive for PV/LPV in a DNA damage repair (DDR) gene ( P= 0.044). Conclusions: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. A FDR with PCa was predictive for PV/LPV in DDR genes. These data emphasize the contribution of FH to germline genetic testing results in a cohort with complete ascertainment of cancer in first degree relatives.

scholarly journals Outbreak of Colistin-Resistant, Carbapenem-ResistantKlebsiella pneumoniaein Metropolitan Detroit, Michigan

2010 ◽  
Vol 55 (2) ◽  
pp. 593-599 ◽  
Author(s):  
Dror Marchaim ◽  
Teena Chopra ◽  
Jason M. Pogue ◽  
Federico Perez ◽  
Andrea M. Hujer ◽  
...  
Keyword(s):  
Gel Electrophoresis ◽  
Index Case ◽  
Medical Center ◽  
The United States ◽  
Pulsed Field Gel Electrophoresis ◽  
Pharmacy Records ◽  
Carbapenem Resistant ◽  
The Mean ◽  
Repetitive Extragenic Palindromic Pcr ◽  
Repetitive Extragenic Palindromic

ABSTRACTCarbapenem-resistantKlebsiella pneumoniaehas spread worldwide and throughout the United States. Colistin is used extensively to treat infections with this organism. We describe a cluster of colistin-resistant, carbapenem-resistantK. pneumoniaeinfection cases involving three institutions in Detroit, MI. A cluster of five cases of colistin-resistant, carbapenem-resistantK. pneumoniaewas identified at Detroit Medical Center (DMC) from 27 July to 22 August 2009. Epidemiologic data were collected, and transmission opportunities were analyzed. Isolates were genotyped by using pulsed-field gel electrophoresis and repetitive extragenic palindromic PCR. Data regarding the use of colistin were obtained from pharmacy records. The index case of colistin-resistant, carbapenem-resistantK. pneumoniaewas followed 20 days later by four additional cases occurring in a 6-day interval. All of the patients, at some point, had stayed at one particular institution. The mean number of opportunities for transmission between patients was 2.3 ± 0.5, and each patient had at least one opportunity for transmission with one of the other patients. Compared to 60 colistin-susceptible, carbapenem-resistantK. pneumoniaecontrols isolated in the previous year at DMC, case patients were significantly older (P= 0.05) and the carbapenem-resistantK. pneumoniaeorganisms isolated from them displayed much higher MICs to imipenem (P< 0.001). Colistin use was not enhanced in the months preceding the outbreak. Genotyping revealed two closely related clones. This report of a colistin-resistant, carbapenem-resistantK. pneumoniaeoutbreak is strongly linked to patient-to-patient transmission. Controlling the spread and novel emergence of bacteria with this phenotype is of paramount importance.

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