2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Population-Based Incidence Estimates of Classical Homocystinuria Using the Genome Aggregation Database (gnomAD)

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This study presented at the American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting aimed to estimate the population-based incidence of classical homocystinuria (HCU) using the Genome Aggregation Database (gnomAD). HCU is a genetic disease caused by pathogenic variants in the cystathionine beta-synthase (CBS) gene and is characterized by developmental delay, vision problems, skeletal abnormalities, and thromboembolism.<br /><br />The researchers obtained variant information from various databases and literature resources, including ClinVar, Human Gene Mutation Database (HGMD), and gnomAD. They identified 1,294 variants, of which 116 were deemed pathogenic and used to calculate HCU incidence estimates. The estimated incidence varied across populations, with the highest estimates in populations with well-characterized variation. The incidence ranged from 1 in 65,000 in the European non-Finnish population to 1 in 4,000,000 in the East Asian population.<br /><br />The study found that the calculated incidence of HCU in populations with well-characterized variation was higher than historical estimates and aligned with real-world healthcare evidence. However, the researchers noted that their approach may have underestimated the incidence in populations with fewer characterized variants.<br /><br />The study also discussed the methodology used, including manual curation to minimize false positives and negatives, and the assumptions made in the calculation, such as the Hardy-Weinberg principle and 100% penetrance of variants.<br /><br />In conclusion, this study provided estimates of HCU incidence based on population allele frequencies and highlighted the variability in incidence across different populations. The findings suggest that the prevalence of HCU may be underestimated, particularly in populations with limited representation in characterized variants.

Asset Subtitle

Submitter Only - Melissa Speer, BSc; Presenting Author - Tiziano Pramparo, PhD; Co-Author - Henk J. Blom, PhD; Co-Author - Ida Vanessa D. Schwartz, MD, PhD; Co-Author - Steve Rodems, PhD; Co-Author - Frederick P. Roth, PhD;

Meta Tag

Biochemical genetics

Databases

Etiology

Genetic Diversity

Genetic Testing

Metabolic Disorder

Population Genetics

Co-Author Henk J. Blom, PhD

Co-Author Ida Vanessa D. Schwartz, MD, PhD

Co-Author Steve Rodems, PhD

Co-Author Frederick P. Roth, PhD

Presenting Author Tiziano Pramparo, PhD

Submitter Only Melissa Speer, BSc

Keywords

classical homocystinuria

HCU

Genome Aggregation Database

gnomAD

cystathionine beta-synthase

CBS gene

incidence estimates

population-based incidence

pathogenic variants

allele frequencies