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Population Frequency of Undiagnosed Fabry Disease in the General Population
Amalia Kermond-Marino1, Annie Weng1, Selina Kai Xi Zhang1
1Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne Victoria, Australia.
Insights
Fabry disease, caused by pathogenic GLA variants, is more common than previously thought, affecting approximately 1 in 3225 individuals. This X-linked disorder remains underdiagnosed, particularly in women.
Area of Science:
- Genetics
- Rare Diseases
- Population Health
Background:
- Fabry disease is an X-linked genetic disorder caused by pathogenic variants in the GLA gene, treatable with modern therapies.
- Previous population frequency studies for Fabry disease primarily focused on males or specialized clinic attendees, potentially underestimating its prevalence.
- The Genome Aggregation Database (gnomAD) provides a valuable resource for investigating the population frequency of rare genetic disorders.
Purpose of the Study:
- To determine the prevalence of undiagnosed Fabry disease within the general population.
- To identify predicted pathogenic GLA variants in the gnomAD database to estimate Fabry disease frequency.
- To assess the underdiagnosis of Fabry disease, especially in women.
Main Methods:
- Examined the gnomAD database for predicted pathogenic GLA variants using rarity, transcript effect prediction tools (CADD, PP2, SIFT, Mutation Taster), and amino acid conservation analysis.
- Utilized computational tools to filter variants based on predicted pathogenicity criteria.
- Compared variant frequencies across different ancestries and with existing Fabry disease databases.
Main Results:
- Predicted pathogenic GLA variants were identified in approximately 1 in 3225 individuals in the gnomAD population.
- A higher prevalence of predicted pathogenic variants was observed in females (3.1:1 ratio), suggesting underdiagnosis in women.
- No predicted pathogenic variants were found in individuals of South Asian, Ashkenazi, or Finnish ancestry.
Conclusions:
- Fabry disease is more prevalent in the general population than previously recognized, with an estimated frequency of 1 in 3225.
- The study highlights significant underdiagnosis of Fabry disease, particularly among women.
- The findings underscore the need for broader screening and awareness of Fabry disease across diverse populations.
Introduction:
Fabry disease is an X-linked disorder that results from pathogenic GLA variants and can now be treated. Most studies of its population frequency have examined only males or attendees at kidney failure or cardiac clinics. This study determined the prevalence of undiagnosed Fabry disease from predicted pathogenic GLA variants in the general population.
Methods:
The Genome Aggregation Database (gnomAD) was examined for predicted pathogenic GLA variants based on variant rarity (≤5), and transcript effect in 4 computational tools (CADD >20, PP2 >0.95, SIFT <0.05, Mutation Taster - Disease-causing) and amino acid conservation in vertebrates in a Clustal.
Results:
Predicted pathogenic variants in GLA occurred in 1 in 3225 of the gnomAD population and 1 in 3478 of its control subset. Predicted pathogenic variants were more common in women than expected (3.1:1), which is consistent with men being excluded from gnomAD because of Fabry complications. Predicted pathogenic variants were not found in members of this cohort with South Asian, Ashkenazim, or Finnish ancestries. Variants identified as pathogenic in the Fabry database were found in 1 in 2651 individuals of the gnomAD database and pathogenic variants from ClinVar in 1 in 4420.
Discussion:
The population frequency of 1 in 3225 for undiagnosed men and women with Fabry disease still represents an underestimate because our pathogenicity criteria were rigorous, the cohort did not include already-diagnosed individuals, and whole exome sequencing does not detect intronic variants and large deletions. This study confirms that Fabry disease is more common than previously recognized and still underdiagnosed especially in women.
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