Harmonizing the Collection of Clinical Data on Genetic Testing Requisition Forms to Enhance Variant Interpretation in Hypertrophic Cardiomyopathy (HCM)

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care. Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care. Patient phenotype is a common field on laboratory requisition forms. As an item of the College of American Pathologists checklist for laboratory results classification (https://elss.cap.org/elss/ShowProperty?nodePath=/UCMCON/Contribution%20Folders/DctmContent/education/OnlineCourseContent/2017/LAP-TLTM/checklists/cl-mol.pdf, last accessed August 7, 2020), a patient's phenotypic data not only may be taken into consideration when providing a clinical interpretation of a result by the health care provider, but they also may aid in variant classification.1Giudicessi J.R. Lieve K.V.V. Rohatgi R.K. Koca F. Tester D.J. van der Werf C. Martijn Bos J. Wilde A.A.M. Ackerman M.J. Assessment and validation of a phenotype-enhanced variant classification framework to promote or demote RYR2 missense variants of uncertain significance.Circ Genom Precis Med. 2019; 12: e002510Crossref PubMed Scopus (16) Google Scholar This has become increasingly critical with the continued expansion of genetic testing, resulting in ever-growing volumes of genomic data to analyze. Guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology on sequence variant classification2Richards S. Aziz N. Bale S. Bick D. Das S. Gastier-Foster J. Grody W.W. Hegde M. Lyon E. Spector E. Voelkerding K. Rehm H.L. on behalf of the ACMG Laboratory Quality Assurance CommitteeStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-423Crossref PubMed Scopus (10318) Google Scholar emphasize the importance of case-level data for phenotype-supported proband (PS4 and PP4), segregation (PP1), and de novo occurrence criteria (PS2 and PM6) that are used in variant interpretation. This is illustrated by MYH7 p.Ala1379Thr, which would have remained a variant of uncertain significance without the availability of phenotype-based case data,3Walsh R. Thomson K.L. Ware J.S. Funke B.H. Woodley J. McGuire K.J. Mazzarotto F. Blair E. Seller A. Taylor J.C. Minikel E.V. MacArthur D.G. Farrall M. Cook S.A. Watkins H. Exome Aggregation ConsortiumReassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.Genet Med. 2017; 19: 192-203Crossref PubMed Scopus (335) Google Scholar, 4Zou Y. Wang J. Liu X. Wang Y. Chen Y. Sun K. Gao S. Zhang C. Wang Z. Zhang Y. Feng X. Song Y. Wu Y. Zhang H. Jia L. Wang H. Wang D. Yan C. Lu M. Zhou X. Song L. Hui R. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy.Mol Biol Rep. 2013; 40: 3969-3976Crossref PubMed Scopus (46) Google Scholar, 5Richard P. Charron P. Carrier L. Ledeuil C. Cheav T. Pichereau C. Benaiche A. Isnard R. Dubourg O. Burban M. Gueffet J.-P. Millaire A. Desnos M. Schwartz K. Hainque B. Komajda M. 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Multiple gene variants in hypertrophic cardiomyopathy in the era of next-generation sequencing.Circ Cardiovasc Genet. 2017; 10: e001666Crossref PubMed Scopus (47) Google Scholar including segregation with hypertrophic cardiomyopathy (HCM) across three families with a total of 15 affected relatives.8Blair E. Redwood C. de Jesus Oliveira M. Moolman-Smook J.C. Brink P. Corfield V.A. Ostman-Smith I. Watkins H. Mutations of the light meromyosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy.Circ Res. 2002; 90: 263-269Crossref PubMed Scopus (76) Google Scholar As medical genetics is increasingly incorporated into routine clinical practice, diagnostic laboratories have been able to obtain phenotypic data from ordering providers and are in a position to be major contributors to variant knowledge because of the large number of cases that are processed. Wain et al9Wain K.E. Palen E. Savatt J.M. Shuman D. Finucane B. Seeley A. Challman T.D. Myers S.M. Martin C.L. The value of genomic variant ClinVar submissions from clinical providers: beyond the addition of novel variants.Hum Mutat. 2018; 39: 1660-1667Crossref PubMed Scopus (7) Google Scholar emphasized this concept, highlighting the importance of submitting phenotype information to laboratories. The utility of harmonized case-level phenotypic data is twofold:(1)Outside of rare disease and whole exome/genome testing, laboratories typically do not need extensive phenotypic data for processing a specific case (as the emphasis is not to diagnose a patient, but rather to provide an interpretation of sequence findings). However, certain phenotypic data elements can prove helpful in refining the clinical interpretation of variants. Variant classification in HCM requires phenotype and family history information, such as documentation of syndromic features, evidence of physiological remodeling, absence of family history of HCM,10Ingles J. Burns C. Bagnall R. Lam L. Yeates L. Sarina T. Puranik R. Briffa T. Atherton J. Driscoll T. Semsarian C. Non-familial hypertrophic cardiomyopathy: prevalence, natural history and clinical implications.J Am Coll Cardiol. 2017; 69: 839Crossref Google Scholar or increased disease severity (which may be due to multiple variants) that is not usually obtained to establish a clinical diagnosis. Given these complexities, a simple check mark in a box on a requisition form indicating a diagnosis of HCM is often insufficient.(2)Similar to aggregating published case-level data, it is increasingly recognized that combining unpublished case data internal to each laboratory across laboratories can significantly improve variant classification.11Kelly M.A. Caleshu C. Morales A. Buchan J. Wolf Z. Harrison S.M. Cook S. Dillon M.W. Garcia J. Haverfield E. Jongbloed J.D.H. Macaya D. Manrai A. Orland K. Richard G. Spoonamore K. Thomas M. Thomson K. Vincent L.M. Walsh R. Watkins H. Whiffin N. Ingles J. van Tintelen J.P. Semsarian C. Ware J.S. Hershberger R. Funke B. for the ClinGen Cardiovascular Clinical Domain Working GroupAdaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel.Genet Med. 2018; 20: 351-359Crossref PubMed Scopus (138) Google Scholar,12Ho C.Y. Day S.M. Ashley E.A. Michels M. Pereira A.C. Jacoby D. Cirino A.L. Fox J.C. Lakdawala N.K. Ware J.S. Caleshu C.A. Helms A.S. Colan S.D. Girolami F. Cecchi F. Seidman C.E. Sajeev G. Signorovitch J. Green E.M. Olivotto I. for the SHaRe InvestigatorsGenotype and lifetime burden of disease in hypertrophic cardiomyopathy.Circulation. 2018; 138: 1387-1398Crossref PubMed Scopus (187) Google Scholar However, although laboratories have been successful at collecting phenotypic data, they have operated in isolation without consensus standards on what information is most critical, hampering their ability to harness the power of aggregate data. In the case of HCM, clinical diagnostic criteria are published. Both the American Heart Association/American College of Cardiology13Gersh B.J. Maron B.J. Bonow R.O. Dearani J.A. Fifer M.A. Link M.S. Naidu S.S. Nishimura R.A. Ommen S.R. Rakowski H. Seidman C.E. Towbin J.A. Udelson J.E. Yancy C.W. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular and Society of Thoracic for the diagnosis and of hypertrophic cardiomyopathy: a of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Cardiovasc PubMed Scopus Google Scholar and the Society of A. M.A. M. Cecchi F. Charron P. A. G. H. J. P. S. B. C. C. Watkins H. Force guidelines on diagnosis and of hypertrophic cardiomyopathy: the Task Force for the diagnosis and of hypertrophic cardiomyopathy of the Society of Cardiology Heart J. PubMed Scopus Google Scholar guidelines that HCM is defined as a of that of to may be in the of disease or a genetic However, these the Society of Cardiology of HCM left ventricular hypertrophy in the absence of a the American Heart Association/American College of Cardiology also requires of or In the has not the of clinical information that is The of consensus on what phenotypic data are and for genetic testing results has not been in the by Cardiomyopathy Variant Curation Expert to as the ClinGen Expert this study was set to determine the phenotypic data elements to affected for a case variant classification and enhance the ability to cases variant classification for of the expert a of data elements typically in and in requisition forms. 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Rehm H.L. on behalf of the ACMG Laboratory Quality Assurance CommitteeStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-423Crossref PubMed Scopus (10318) Google by the Expert data elements pilot laboratories of data, and and elements deemed essential for variant and diagnosis of at ventricular ventricular hypertrophy ventricular ejection of on syndromic with left ventricular hypertrophy or of ventricular on on HCM, hypertrophic Laboratory for Molecular in a HCM, hypertrophic Laboratory for Molecular the of across laboratory requisition forms used in the of the last accessed August was for laboratories testing for The requisition forms were from their and each field was were to fields that were common across laboratories. fields data but using were was A pilot study was to in providing data on requisition forms and to determine the feasibility of harmonizing laboratory requisition forms on the expert phenotypic data The pilot study of 50 cases for HCM testing to the Laboratory for Molecular a and The requisition fields on the form were to the expert data elements a field was completed by the ordering provider, it was as of the from the case requisition a Laboratory was by the study and and in the of to determine the criteria were essential and for variant classification were from laboratories cardiomyopathy genetic testing that also used expert or was laboratory directors to and to provide was and were that only aggregate data would be The a clinical molecular as a laboratory genetic an to the this and as of their to the expert were to of of was defined as a with a that genetic testing or there be a in a gene and variant may be to have an of when they have in or the of knowledge a gene or The consensus of and the of the results of the Laboratory a was by study Expert Panel including in which of the criteria was and was to of the ClinGen Expert Panel on and on The to were that of a was as of the was defined as from at of the results were ClinGen Expert Panel at which consensus was A total of data elements were across requisition forms from nine laboratories of fields showed that the criteria on the expert were not across laboratories. there were in the of phenotypic data by on in history genetic family history history history number of at of history field for clinical at Cardiomyopathy diagnosis diagnostic criteria for diagnosis of of genetic genetic or or result or fraction, of Heart Cardiovascular or at HCM, hypertrophic left in a HCM, hypertrophic left such as demographics and family were on most requisition forms. 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