Population Frequency of Undiagnosed Fabry Disease in the General Population

Kidney Int Rep. 2023 Apr 17;8(7):1373-1379. doi: 10.1016/j.ekir.2023.04.009.

PMID: 37441486

Amalia Kermond-Marino, Annie Weng, Selina Kai Xi Zhang

Highlights: This study confirms that Fabry disease is more common than previously recognized and still underdiagnosed especially in women.

Abstract

Introduction: Pathogenic GLA variants cause the X-linked disorder known as Fabry disease, which is now treatable. The majority of population frequency studies have only looked at men or patients 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: Based on variant rarity (5), transcript effect in 4 computational methods (CADD >20, PP2 >0.95, SIFT 0.05, Mutation Taster - Disease-causing), and amino acid conservation in vertebrates in a Clustal, predicted pathogenic GLA variants were searched for in the Genome Aggregation Database (gnomAD).

Results: In the gnomAD population and its control subset, predicted pathogenic variants in GLA were found in 1 in 3225 and 1 in 3478, respectively. Predicted pathogenic variants were found in women more frequently than in males (3.1:1), which is consistent with men being excluded from gnomAD due to Fabry complications. Members of this group with South Asian, Ashkenazi, or Finnish ancestry did not have predicted pathogenic variants. In the gnomAD database, 1 in 2651 people had pathogenic variants identified in the Fabry database, and 1 in 4420 people had pathogenic variants identified in the ClinVar database.

Discussion: Because the pathogenicity criteria of this study were strict, the cohort did not include people who had already received a diagnosis, and whole exome sequencing does not detect intronic variants and large deletions, the population frequency of 1 in 3225 for undiagnosed men and women with Fabry disease still represents an underestimate. This study reveals that Fabry disease is underdiagnosed and more prevalent than previously thought, particularly in women.

Keywords: Fabry disease, GLA variant, Genome Aggregation Database