Kidney Week

Abstract: SA-PO0201

INF2 Pathogenic Variant and FN1 Variant of Uncertain Significance in Familial Glomerulopathy: Insights from Integrated Genotype-Phenotype Correlation

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

• Yandian, Federico, Médica Uruguaya, Montevideo, Uruguay

Federico Yandian, MD

• Raggio, Víctor E., Facultad de Medicina, UDELAR, Montevideo, Uruguay

Víctor E. Raggio, MD

• Dominguez, Maria Fernanda /F, Facultad de Medicina, UDELAR, Montevideo, Uruguay

Maria Fernanda /F Dominguez, PhD

• Spangenberg, Lucia, Institut Pasteur, Montevideo, Montevideo, Uruguay

Lucia Spangenberg, PhD

• Simoes Amaro, Camila S., Institut Pasteur, Montevideo, Montevideo, Uruguay

Camila S. Simoes Amaro, MSc

• Facal, Lucia, Médica Uruguaya, Montevideo, Uruguay

Lucia Facal, MD

• Boggia, Jose, Hospital de Clínicas "Dr. Manuel Quintela", Montevideo, Uruguay

Jose Boggia, MD, MS, MSc, PhD

Introduction

The increasing availability of exome sequencing has expanded recognition of monogenic kidney diseases; however, the contribution of additional variants to phenotypic variability remains unclear.

Case Description

We describe a family with a strong history of kidney disease in which 7 affected individuals and unaffected relatives underwent exome sequencing. Affected individuals met criteria for chronic kidney disease (CKD), defined by persistent abnormalities including estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, proteinuria >0.3 g/day, and/or microhematuria. Among them, 4 had eGFR <60 mL/min/1.73 m2, including 2 who progressed to kidney failure requiring renal replacement therapy. A heterozygous pathogenic INF2 variant (NM_001031714; c.530G>A; p.Arg177His) showed complete segregation (7/7 affected; 0/2 unaffected), consistent with autosomal dominant inheritance. Additionally, a heterozygous FN1 variant (NM_212482; c.1123A>G; p.Thr375Ala) was detected. This variant is extremely rare (gnomAD AF 1.5×10-5), not previously associated with kidney phenotypes, predicted deleterious (CADD 26.6; REVEL 0.745), but classified as a variant of uncertain significance. Notably, all individuals with more advanced CKD carried both variants, whereas milder phenotypes were observed in those carrying only INF2 variant. No extrarenal manifestations were identified. Kidney biopsy (n=3) showed mesangial expansion in one patient with the INF2 variant and focal segmental glomerulosclerosis in two individuals harbouring both variants, one demonstrating subendothelial fibronectin deposits. Mean age was 51 years (range 34–68). The two patients who progressed to kidney failure initiated renal replacement therapy at 37 and 49 years. All studied individuals were female; however, several affected, non-genotyped relatives requiring renal replacement therapy were male, arguing against an X-linked pattern.

Discussion

This is the first report of co-occurring INF2 and FN1 variants in a single family. While INF2 likely drives the primary disease, more severe phenotypes in dual-variant carriers suggest modifying effect of FN1. This case highlights the impact of additional variants on disease severity in inherited glomerulopathies. Integrated genotype–phenotype correlation is essential as multi-variant findings become increasingly common in clinical practice.