Browsing by Author "Sijbrands, Eric J."
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- Adaptation of ACMG/AMP guidelines for standardized variant interpretation in familial hypercholesterolemiaPublication . Iacocca, Michael A.; Chora, Joana R.; Freiberger, Tomas; Carrie, Alain; Leigh, Sarah E.; Kurtz, C. Lisa; Tichy, Lukas; DiStefano, Marina T.; Wand, Hannah; Defesche, Joep; Sijbrands, Eric J.; Hegele, Robert A; Knowles, Joshua W.; Bourbon, Mafalda; On behalf of the ClinGen FH Variant Curation Expert PanelBackground: The successes of clinical genetics rely on accurate DNA variant interpretation for the purpose of informing diagnosis and treatment; However, this practice is often rudimentary and differs among diagnostic laboratories, leading to inconsistencies in pathogenicity classification: In response, the Clinical Genome (ClinGen) Resource consortium approves expert panels to recommend disease-specific guidelines to achieve evidence-based, standardized variant curation practice.
- Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert PanelPublication . Sturm, Amy C.; Knowles, Joshua W.; Gidding, Samuel S.; Ahmad, Zahid S.; Ahmed, Catherine D.; Ballantyne, Christie M.; Baum, Seth J.; Bourbon, Mafalda; Carrié, Alain; Cuchel, Marina; de Ferranti, Sarah D.; Defesche, Joep C.; Freiberger, Tomas; Hershberger, Ray E.; Hovingh, G. Kees; Karayan, Lala; Kastelein, Johannes Jacob Pieter; Kindt, Iris; Lane, Stacey R.; Leigh, Sarah E.; Linton, MacRae F.; Mata, Pedro; Neal, William A.; Nordestgaard, Børge G.; Santos, Raul D.; Harada-Shiba, Mariko; Sijbrands, Eric J.; Stitziel, Nathan O.; Yamashita, Shizuya; Wilemon, Katherine A.; Ledbetter, David H.; Rader, Daniel J.; convened by the Familial Hypercholesterolemia FoundationAlthough awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.
- ClinVar database of global familial hypercholesterolemia-associated DNA variantsPublication . Iacocca, Michael A.; Chora, Joana R.; Carrié, Alain; Freiberger, Tomáš; Leigh, Sarah E.; Defesche, Joep C.; Kurtz, C. Lisa; DiStefano, Marina T.; Santos, Raul D.; Humphries, Steve E.; Mata, Pedro; Jannes, Cinthia E.; Hooper, Amanda J.; Wilemon, Katherine A.; Benlian, Pascale; O'Connor, Robert; Garcia, John; Wand, Hannah; Tichy, Lukáš; Sijbrands, Eric J.; Hegele, Robert A.; Bourbon, Mafalda; Knowles, Joshua W.; on behalf of the ClinGen FH Variant Curation Expert PanelAccurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.
- Familial hypercholesterolemia-associated variants submitted to ClinVar: a ClinGen FH effortPublication . Rita Chora, Joana; Iacocca, Michael A.; DiStefano, Marina T.; Carrie, Alain; Freiberger, Tomas; Leigh, Sarah E.; Kurtz, C. Lisa; Defesche, Joep; Sijbrands, Eric J.; Hegele, Robert A.; Knowles, Joshua W.; Bourbon, Mafalda; on behalf of the ClinGen FH Variant Curation CommitteeFamilial hypercholesterolemia (FH) is an autosomal dominant disorder of lipid metabolism characterized by elevated levels of LDL-C and increased cardiovascular risk. A vast number of potentially pathogenic variants have been identified in FH patients in LDLR, APOB, and PCSK9 genes. We sought to encourage FH researchers/clinicians worldwide to submit their variant findings to the centralized ClinVar database, with the ultimate goal of achieving accurate and consistent variant classification through data sharing and eventual development of FH-specific variant interpretation guidelines.
- Familial hypercholesterolemiaassociated variants in ClinVarPublication . Chora, Joana R.; Iacocca, Michael A.; Carrié, Alain; Freiberger, Tomáš; Leigh, Sarah E.; Defesche, Joep C.; Kurtz, C. Lisa; DiStefano, Marina T.; Santos, Raul D.; Humphries, Steve E.; Mata, Pedro; Jannes, Cinthia E.; Hooper, Amanda J.; Wilemon, Katherine A.; Benlian, Pascale; O'Connor, Robert; Garcia, John; Wand, Hannah; Tichý, Lukáš; Sijbrands, Eric J.; Hegele, Robert A.; Bourbon, Mafalda; Knowles, Joshua W.; On behalf of the ClinGen FH Variant Curation Expert PanelFamilial Hypercholesterolemia (FH): Lipid metabolism autosomal dominant condition; Patients present elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) values since birth - elevated cardiovascular risk if untreated; High heterozygote prevalence (1/250-500); Homozygous rare (1/300 000-1 000 000); Caused by pathogenic variants in LDLR (>90%), APOB (5-10%) and PCSK9 (1-3%) genes.
- Progress in ACMG/AMP-adapted guidelines for standardized variant curation in familial hypercholesterolemiaPublication . Iacocca, Michael A.; Chora, Joana; Rivera, E. Andy; DiStefano, Marina T.; Carrie, Alain; Sijbrands, Eric J.; Defesche, Joep; Freiberger, Tomas; Knowles, Joshua W.; Hegele, Robert A.; Bourbon, MafaldaBackground: - The successes of clinical genetics rely on accurate variant interpretation for the purpose of informing diagnosis and treatment: - However, this practice is often rudimentary and differs among diagnostic laboratories, leading to inconsistencies in pathogenicity classification; - In response, the Clinical Genome Resources (ClinGen) consortium approves expert panels to recommend disease-specific guidelines to achieve evidence-based, standardized variant curation practice. Familial Hypercholesterolemia (FH) Working Group: - FH is a prevalent monogenic disorder, affecting ~1/250 individuals; - It is characterized by extreme LDL cholesterol levels and premature atherosclerosis causing cardiovascular disease; - Genetic testing is increasingly offered worldwide as a central part of diagnosis.
- Specification of ACMG AMP Guidelines for Variant Interpretation in Familial HypercholesterolemiaPublication . Chora, Joana R.; Lacocca, Michael A.; Carrié, Alain; Leigh, Sarah E.; Tichý, Lukáš; Kurtz, C. Lisa; Freiberger, Tomas; Sijbrands, Eric J.; Hegele, Robert A.; Knowles, Joshua W.; Bourbon, MafaldaBackground and Aims: the general ACMG/AMP guidelines for standardized variant interpretation in Mendelian disorders are a great asset in determining variants’ pathogenicity, but need to be adapted to each specific gene and disease.
- The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classificationPublication . Chora, Joana R.; Iacocca, Michael A.; Tichý, Lukáš; Wand, Hannah; Kurtz, C. Lisa; Zimmermann, Heather; Leon, Annette; Williams, Maggie; Humphries, Steve E.; Hooper, Amanda J.; Trinder, Mark; Brunham, Liam R.; Costa Pereira, Alexandre; Jannes, Cinthia E.; Chen, Margaret; Chonis, Jessica; Wang, Jian; Kim, Serra; Johnston, Tami; Soucek, Premysl; Kramarek, Michal; Leigh, Sarah E.; Carrié, Alain; Sijbrands, Eric J.; Hegele, Robert A.; Freiberger, Tomáš; Knowles, Joshua W.; Bourbon, Mafalda; ClinGen Familial Hypercholesterolemia Expert PanelPurpose: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified. Methods: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached. Results: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others. Conclusion: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.