Kidney Week

Abstract: SA-PO0146

Unmasking a Variant of Uncertain Significance in Fabry Disease: Report of Two Familial Cases with a Classic Phenotype

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

• Arenas Moncaleano, Iván, Section of Nephrology and Hypertension, Hospital General Universitario Nuestra Señora del Prado, Talavera de la Reina, Spain

Iván Arenas Moncaleano, MD

• Guerra-Torres, Xavier E., Section of Nephrology and Hypertension, Hospital General Universitario Nuestra Señora del Prado, Talavera de la Reina, Spain

Xavier E. Guerra-Torres, MD

• Monroy Condori, Maribel, Section of Nephrology and Hypertension, Hospital General Universitario Nuestra Señora del Prado, Talavera de la Reina, Spain

Maribel Monroy Condori, MD

• Morales Montoya, Jorge Luis, Section of Nephrology and Hypertension, Hospital General Universitario Nuestra Señora del Prado, Talavera de la Reina, Spain

Jorge Luis Morales Montoya, MEd

• Ivars, Alberto Galiana, Service of Neurology, Hospital General Universitario Nuestra Señora del Prado, Talavera de la Reina, Spain

Alberto Galiana Ivars

Group or Team Name

• Grupo de estudio de Enfermedad de Fabry

Introduction

Fabry disease (FD) results from X-linked lysosomal α-galactosidase A deficiency. Interpreting ultra-rare GLA variants of uncertain significance remains clinically challenging. We report a mother and son carrying the c.731A>T (p.Asp244Val) variant. Integrating deep phenotyping, histopathology, and segregation analysis per ACMG/ClinGen criteria supported reclassifying the variant as likely pathogenic.

Case Description

Case 1 (index) is a 63-year-old female presenting with hypertrophic cardiomyopathy, stroke, and cornea verticillata. High lyso-Gb3 levels and low α-galactosidase A activity accompanied mild renal involvement (eGFR 69 mL/min/1.73m2; uACR 113 mg/g). Renal biopsy confirmed characteristic Fabry inclusions (Figure 1). Her son (Case 2) is a hemizygous carrier exhibiting cornea verticillata, a short PR interval, <1% enzyme activity, and albuminuria (uACR 183 mg/g). Integrating genetic, phenotypic, histological, and familial evidence (PM5, PP4, PM2, PP1, PP3), we reclassified the variant as likely pathogenic. Both patients initiated agalsidase beta therapy (1 mg/kg every 14 days). Lyso-Gb3 levels decreased from 10.9 to 4.9 ng/mL (Case 1) and 64.5 to 11.5 ng/mL (Case 2). Case 1 achieved albuminuria regression without cardiovascular events. Case 2 experienced relief from gastrointestinal symptoms with stable eGFR.

Discussion

This case shows that integrating renal biopsy, multimodal phenotyping, and family segregation provides evidence to resolve diagnostic uncertainty and support the reinterpretation of ultra-rare GLA variants. Our findings are potentially relevant for future updates to the ClinVar database.

Figure 1. Renal biopsy. A: H&E staining of glomeruli showing microvacuolar changes within podocytes. B: Toluidine blue staining revealing intracytoplasmic inclusions within podocytes. C: Capillary loops exhibiting podocyte foot process effacement. C & D: Myelin bodies observed within the cytoplasm.