Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels
| العنوان: | Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels |
|---|---|
| المؤلفون: | Meera K. Jairath, Sarah E. Brnich, Chris Bizon, Bradford C. Powell, Jonathan S. Berg, Shannon M. McNulty, Dona M. Kanavy |
| المصدر: | Genome Medicine, Vol 11, Iss 1, Pp 1-19 (2019) Genome Medicine |
| بيانات النشر: | BMC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Functional assay, medicine.medical_specialty, lcsh:QH426-470, Computer science, Process (engineering), Systems biology, Clinical genome sequencing, lcsh:Medicine, Genomics, Computational biology, Disease, 03 medical and health sciences, Consistency (database systems), 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Functional studies, Genetic Testing, Molecular Biology, Expert Testimony, Genetics (clinical), Variant interpretation, 030304 developmental biology, Functional assays, 0303 health sciences, Mechanism (biology), Research, lcsh:R, Disease Management, Genetic Variation, Human genetics, Clinical exome sequencing, lcsh:Genetics, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, Molecular Medicine, Medical genetics, Disease Susceptibility, Medical Informatics, Software, Clinical genome resource |
| الوصف: | BackgroundThe 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that “well-established” functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays. We set out to evaluate the existing VCEP guidelines for functional assays.MethodsWe evaluated the functional criteria (PS3/BS3) of six VCEPs (CDH1, Hearing Loss, Inherited Cardiomyopathy-MYH7,PAH,PTEN, RASopathy). We then established criteria for evaluating functional studies based on disease mechanism, general class of assay, and the characteristics of specific assay instances described in the primary literature. Using these criteria, we extensively curated assay instances cited by each VCEP in their pilot variant classification to analyze VCEP recommendations and their use in the interpretation of functional studies.ResultsUnsurprisingly, our analysis highlighted the breadth of VCEP-approved assays, reflecting the diversity of disease mechanisms among VCEPs. We also noted substantial variability between VCEPs in the method used to select these assays and in the approach used to specify strength modifications, as well as differences in suggested validation parameters. Importantly, we observed discrepancies between the parameters VCEPs specified as required for approved assay instances and the fulfillment of these requirements in the individual assays cited in pilot variant interpretation.ConclusionsInterpretation of the intricacies of functional assays often requires expert-level knowledge of the gene and disease, and current VCEP recommendations for functional assay evidence are a useful tool to improve the accessibility of functional data by providing a starting point for curators to identify approved functional assays and key metrics. However, our analysis suggests that further guidance is needed to standardize this process and ensure consistency in the application of functional evidence. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c8ad7485e9a1ddf2479db2fdba976cd9 https://doaj.org/article/953cd458b6704122b1525cfebd52050e |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c8ad7485e9a1ddf2479db2fdba976cd9 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |