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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Use of population data to empower patient organiza ...
Use of population data to empower patient organizations and improve advocacy for rare disease therapeutics
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This document discusses the estimation of disease prevalence for rare recessive genetic disorders using variant databases. The prevalence of most rare diseases is still unknown, but it is important for advocacy groups and organizations to have this information for therapy development and advocacy purposes. The study used population variant data to estimate disease prevalence for autosomal recessive conditions in collaboration with the Chan Zuckerberg Rare as One Network.<br /><br />The study collected candidate pathogenic variants from three sources: ClinVar, HGMD, and gene-specific variant databases. Variants present in gnomAD were re-curated following classification guidelines and loss of function variants were curated using a specific protocol. The final list of variants was used to calculate allele frequencies across all populations in gnomAD with over 2,000 alleles. Genetic prevalence was calculated using Hardy-Weinberg principles.<br /><br />The study emphasizes the importance of considering key variables that impact the results, such as missing or underrepresented populations, inclusion of hypomorphs or misclassified variants, and the novelty of the gene. Factors like symptomatic carriers, impacts to life expectancy, reduced penetrance, and variable expressivity should also be considered when reviewing the results.<br /><br />The organizations involved in the study used the results to prioritize variants for functional studies and drug development, educate the clinical community, extend outreach, and approach pharmaceutical companies. The results were returned directly to the patient organizations through Zoom calls accompanied by written materials.<br /><br />Overall, this study highlights the use of variant databases to estimate genetic disease prevalence for rare recessive diseases and provides insights into the process and considerations involved in such estimations.
Asset Subtitle
Presenting Author - Samantha Baxter, MS, CGC; Co-Author - Moriel Singer-Berk, MS; Co-Author - Kathryn Russell, BS; Co-Author - Emily Groopman, MD, PhD; Co-Author - Nick Watts, MS; Co-Author - Michael Wilson, BS; Co-Author - Jordan C. Wood, BS; Co-Author - Heidi L. Rehm, PhD; Co-Author - Anne O'Donnell-Luria, MD, PhD;
Meta Tag
Exome sequencing
Genetic Diversity
Genome sequencing
Population Genetics
Public Patient and Professional Education
Co-Author
Moriel Singer-Berk, MS
Co-Author
Kathryn Russell, BS
Co-Author
Emily Groopman, MD, PhD
Co-Author
Nick Watts, MS
Co-Author
Michael Wilson, BS
Co-Author
Jordan C. Wood, BS
Co-Author
Heidi L. Rehm, PhD
Co-Author
Anne O'Donnell-Luria, MD, PhD
Presenting Author
Samantha Baxter, MS, CGC
Keywords
disease prevalence
rare recessive genetic disorders
variant databases
prevalence estimation
advocacy groups
therapy development
gnomAD
allele frequencies
Hardy-Weinberg principles
functional studies
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