Developing a disease-specific annotation protocol for VHL gene curation using Hypothes.is

Abstract

Von Hippel–Lindau (VHL) disease is a rare, autosomal dominant disorder that predisposes individuals to developing tumors in many organs. There is significant phenotypic variability and genetic variants encountered within this syndrome, posing a considerable challenge to patient care. The lack of VHL variant data sharing paired with the absence of aggregated genotype–phenotype information results in an arduous process, when characterizing genetic variants and predicting patient prognosis. To address these gaps in knowledge, the Clinical Genome Resource (ClinGen) VHL Variant Curation Expert Panel (VCEP) has been resolving a list of variants of uncertain significance within the VHL gene. Through community curation, we crowdsourced the laborious task of variant annotation by modifying the ClinGen Community Curation (C3)-developed Baseline Annotation protocol and annotating all published VHL cases with the reported genotype–phenotype information in Hypothes.is, an open-access web annotation tool. This process, incorporated into the ClinGen VCEP’s workflow, will aid in their curation efforts. To facilitate the curation at all levels of genetics expertise, our team developed a 4-day biocuration training protocol and resource guide. To date, 91.3% of annotations have been completed by undergraduate and high-school students without formal academic genetics specialization. Here, we present our VHL-specific annotation protocol utilizing Hypothes.is, which offers a standardized method to present case-resolution data, and our biocuration training protocol, which can be adapted for other rare disease platforms. By facilitating training for community curation of VHL disease, we increased student engagement with clinical genetics while enhancing knowledge translation in the field of hereditary cancer. Database URL: https://hypothes.is/groups/dKymJJpZ/vhl-hypothesis-annotation

IthaPhen: An Interactive Database of Genotype-Phenotype Data for Hemoglobinopathies

“…The integration of IthaPhen with other databases of the constantly updated ITHANET portal provides the community with a valuable expanding dataset of case‐level data with rich phenotypic annotation and ensures its sustainability. In addition, it will help generate critical evidence for the interpretation of globin gene variants based on the ACMG/AMP framework, an approach also followed by other VCEPs 19 . Furthermore, the integration of EMQN guidelines into IthaPhen facilitates, but does not replace, genetic diagnosis and genetic counseling for hemoglobinopathies, particularly in countries with limited experience and less exposure to hemoglobinopathies.…”

“…In addition, it will help generate critical evidence for the interpretation of globin gene variants based on the ACMG/AMP framework, an approach also followed by other VCEPs. 19 Furthermore, the integration of EMQN guidelines into IthaPhen facilitates, but does not replace, genetic diagnosis and genetic counseling for hemoglobinopathies, particularly in countries with limited experience and less exposure to hemoglobinopathies. Notably, we demonstrated the utility of IthaPhen with 2 examples in (a) genotype-phenotype correlation and (b) standardized variant classification, illustrating how IthaPhen can contribute to data-driven and quantitative approaches in the field of hemoglobinopathies.…”