Abstract: SA-PO0145
Defining the Unique Clinicogenomic Signature of Individuals Carrying the A143T GLA Variant
Session Information
- Tubular, Metabolic, and Systemic Noncystic Genetic Kidney Diseases
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Brudvig, Jon J., Amicus Therapeutics, Inc., Princeton, New Jersey, United States
- Gielen, Vera, Amicus Therapeutics UK Ltd, Marlow, England, United Kingdom
- Benjamin, Elfrida R., Amicus Therapeutics, Inc., Princeton, New Jersey, United States
- Nelson, Matthew, Amicus Therapeutics, Inc., Princeton, New Jersey, United States
- Martin, Richard L., Labcorp (formerly Invitae Corp.), San Francisco, California, United States
- Russell, Emily M., Labcorp (formerly Invitae Corp.), San Francisco, California, United States
- Lacoste, Alix Mary Benedicte, Labcorp (formerly Invitae Corp.), San Francisco, California, United States
- Veleva-Rotse, Biliana O., Amicus Therapeutics, Inc., Princeton, New Jersey, United States
Background
Fabry disease (FD) is a progressive lysosomal disorder caused by GLA gene variants leading to a deficiency of the alpha-galactosidase A (GLA) enzyme. For variants of uncertain significance such as p.Ala143Thr (A143T), real-world clinical manifestation data are limited, with many prior studies underpowered for examining these atypical phenotypes. Large, real-world datasets could provide clarifying evidence on phenotypes and symptom burden. We define the unique signature of individuals with A143T using a US dataset comprising combined, annotated, genomic (Invitae [now part of Labcorp]), and claims and prescription (Komodo Healthcare Map™) data.
Methods
Individuals carrying the GLA A143T variant only (no other pathogenic [P]/likely pathogenic [LP] gene variant) were identified and matched (by age and sex) to two non-overlapping cohorts: GLA P/LP (no other P/LP variant) and Control (no P/LP variant in any gene). Age-adjusted paired US-based claims and prescription data were then analyzed to find enriched International Classification of Diseases (ICD) diagnosis codes (ICD-9/-10); each cohort pair was compared. Enriched codes were sorted into PheCode categories, which map and organize multiple ICD codes into generalized phenotypes, including custom categories (eg pain). Category enrichment was assessed by overrepresentation analysis based on hypergeometric distribution.
Results
Overall, 10,945 individuals were included (females/males A143T: n=176/104; P/LP: n=545/320; Control: n=6160/3640) and had ~10 years' data availability; FD diagnosis rates were 18%/28% (A143T), 70%/78% (P/LP) and 0.2%/0.1% (Control). Versus Control, females carrying P/LP had claims significantly enriched for codes related to sense organs, dermatology and neurology; male P/LP-enriched codes related to genitourinary (including renal), neurology and cardiovascular systems, and blood/immunity. Compared with Control, females carrying A143T had claims significantly enriched in codes related to pregnancy, musculoskeletal and gastrointestinal (GI) systems; in males, significantly enriched A143T codes related to the musculoskeletal system and pain.
Conclusion
PheCode analyses identified enriched typical FD-phenotype-related codes in the P/LP cohort, while those with A143T were significantly enriched for claims related to pain, GI and musculoskeletal systems. This data uncovers a unique and underrecognized A143T clinical presentation.
Funding
- Commercial Support – This study was supported by Amicus Therapeutics, Inc. Medical writing/editorial assistance was provided by Charlotte Marris, PhD, at Amiculum, and was funded by Amicus Therapeutics, Inc.