ClinGen Dosage Sensitivity Curation Module 2024 Version
Date of Release:
Expiration Date: December 31, 2024
Credits offered: CME, NSGC Category 2 (Self-report)
Estimate time of completion: 5 hours per curation (limit of up to 10 curations)
Course must be completed by the expiration date
www.acmgeducation.net
Course Description:
The Clinical Genome Resource (ClinGen, www.clinicalgenome.org) is an NIH-funded resource dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research (Strande et al. 2017). Dosage Sensitivity Curation evaluates genes and genomic regions for haploinsufficiency or triplosensitivity. Haploinsufficiency (HI) is when one copy of a gene or genomic region is lost and results in a consistent phenotype and triplosensitivity (TS) is when there is an extra copy of a gene or genomic region that results in a consistent phenotype. Each gene and genomic region evaluated receives a separate HI score and TS score.
From 2011-2019, the dosage sensitivity curation process was based on the framework published in Riggs et al. 2012. Beginning in February 2019, the group adopted a more stringent evaluation (https://clinicalgenome.org/site/assets/files/6428/dosage_sop-scoring-1.pdf) process for single gene evaluations consistent with the recommendations for evaluating probands identified in the literature, public databases, and/or internal databases (henceforth referred to as “probands”) as described in the American College of Medical Genetics and Genomics (ACMG) and ClinGen technical standards for the interpretation of constitutional CNVs.
There are currently three subgroups within ClinGen’s dosage sensitivity curation team:
- Neurodevelopmental Dosage Subgroup: Evaluating genes implicated in neurodevelopmental disorders (NDDs), including intellectual disability (ID), developmental delays (DD), autism, seizures, etc.
- Hereditary Cancer Subgroup: Evaluating genes implicated in hereditary cancer
- Genomic Regions (Recurrent CNV) Subgroup: Developing additional considerations for the evaluation of recurrent CNVs, including regions associated with low penetrance
The Neurodevelopmental Dosage Subgroup and the Hereditary Cancer Subgroup typically focus on single gene evaluations, while the Recurrent CNV subroup focuses on evaluation of genomic regions with recurrent breakpoints mediated by genomic architecture, such as segmental duplications. In most cases, curators in the group complete the initial dosage sensitivity curation and arrive at a provisional score, followed by presentation of the data to the subgroup for review and final approval.
The Dosage Sensitivity Curation Task Teams utilize the ClinGen Dosage Curation Interface (DCI) for documentation of dosage sensitivity haploinsufficiency and triplosensitivity classifications, and all curations completed by the group are made publicly available through the ClinGen website (clinicalgenome.org).
Target Audience:
This ClinGen Dosage Sensitivity curation module is intended to provide learners with educational credit for participating in ClinGen dosage curation activities and is available to individuals who are existing members of the ClinGen Dosage Sensitivity Working Group and have had at least one dosage curation previously approved by a ClinGen Dosage Sensitivity subgroup.
Learning Objectives:
At the conclusion of this session, participants should be able to:
- Use the ClinGen vetted dosage sensitivity curation process to evaluate the strength of evidence supporting or refuting a claim that variants result in loss of function in a gene of interest
- Perform a literature search to identify relevant publications to support a dosage curation
- Score collected/collated evidence in the DCI to determine a provisional score for haploinsufficiency and triplosensitivity based on guidelines
- Present evidence summary supporting provisional score to dosage sensitivity subgroup
- Publish approved dosage curation to clinicalgenome.org
Course References:
Riggs, E. R., Church, D. M., Hanson, K., Horner, V. L., Kaminsky, E. B., Kuhn, R. M., . . . Martin, C. L. (2012). Towards an evidence-based process for the clinical interpretation of copy number variation. Clinical Genetics, 81(5), 403-412. doi:10.1111/j.1399-0004.2011.01818.x [doi]