Abstract: TH-PO0581
Understanding Severe Kidney Disease in Pediatric Autosomal Dominant Alport Syndrome
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Hager, Megan M., Natera, Inc., Austin, Texas, United States
- Pitman, Tessa R., Natera, Inc., Austin, Texas, United States
- Stein, Quinn, Natera, Inc., Austin, Texas, United States
- Punj, Sumit, Natera, Inc., Austin, Texas, United States
- Valenti, Elizabeth H., Natera, Inc., Austin, Texas, United States
Background
Autosomal Dominant Alport Syndrome (ADAS), caused by heterozygous variants in COL4A3 or COL4A4, is associated with increased risk of adult-onset kidney disease and is uncommon among pediatric patients with kidney dysfunction. Here, we seek to characterize factors associated with severe, early-onset disease in a pediatric ADAS cohort identified on multigene testing for CKD.
Methods
Pediatric patients (<18 years) with (likely) pathogenic (P/LP) COL4A3, COL4A4, or COL4A5 variants identified via RenasightTM (a multigene hereditary kidney panel) between 2019 and 2024 were categorized as having ADAS, X-Linked (XLAS; 1 P/LP variant in COL4A5) or autosomal recessive (ARAS; 2 P/LP variants in COL4A3/4); digenic AS cases were excluded. Those with eGFR <30 at testing were further evaluated for variant type, secondary pathogenic findings and co-diagnoses.
Results
Of 1,544 pediatric patients identified, 58.7% (n=906) had ADAS. 1.4% (13/906) of ADAS cases had an eGFR <30 at testing vs 2.3% (13/577) and 9.6% (5/52) of XLAS and ARAS cases. Among the ADAS cases, most variants were glycine substitutions within COL4A3 (5/7) or COL4A4 (5/6). No variants were enriched in the pediatric cohort, except COL4A4 p.Gly481Ser (p=0.0023, Fisher’s exact test), which was disproportionately observed in Hispanic individuals. 30.8% of ADAS patients (4/13) had secondary positive genetic findings (APOL1, NPHP1, PKD1), and 15.4% (n=2) had secondary diagnoses (C3 Glomerulopathy, unilateral kidney agenesis). Comparatively, 15.4% of XLAS (2/13) and 20% of ARAS (1/5) cases with eGFR <30 had secondary genetic findings and 46.2% of XLAS (6/13) and 60% of ARAS (3/5) cases indicated AS as a reason for testing.
Conclusion
Severe pediatric kidney impairment is rare in ADAS, occurring in 1.4% of our cohort. Our findings suggest secondary genetic findings or diagnoses may exacerbate disease progression, while no specific genotypes were associated with the severe phenotype. The low clinical suspicion of AS and high presence of secondary diagnoses underscores the importance of thorough assessment for other genetic and non-genetic conditions in children with ADAS. Multigene panel testing in children with severe ADAS can facilitate early genetic counseling and timely intervention, helping families manage the long-term effects of inherited kidney disease.
Funding
- Commercial Support – Natera, Inc.