Rare Collagenous Heterozygote Variants in Children With IgA Nephropathy

Area of Science:

• Nephrology
• Genetics
• Pediatric Nephrology

Background:

• Childhood IgA nephropathy (cIgAN) presents with hematuria and proteinuria, potentially overlapping with Alport syndrome.
• Familial IgAN has been linked to chromosome 2q36, encoding collagen type IV alpha 3/4 (COL4A3/A4).

Purpose of the Study:

• To investigate the relationship between Alport syndrome and cIgAN by sequencing COL4A3, COL4A4, and COL4A5 genes in cIgAN patients.
• To determine if COL4A3 variants influence the clinical presentation and progression of cIgAN.

Main Methods:

• Exome sequencing of COL4A3, COL4A4, and COL4A5 in 36 pediatric IgA nephropathy patients.
• Retrospective collection of clinical data and treatment information.
• Classification of identified variants using ACMG/AMP guidelines.

Main Results:

• Four out of 36 cIgAN patients (COL4A3-cIgAN) had pathogenic heterozygous COL4A3 variants (ACMG class 4/5).
• COL4A3-cIgAN patients exhibited active IgAN features, responded to immunosuppression, and showed reduced proteinuria, rather than Alport syndrome.
• These patients demonstrated a predisposition to more severe IgAN, with increased glomerulosclerosis and lower eGFR over time.

Conclusions:

• Pathologic heterozygous COL4A3 variants in cIgAN may predispose to severe disease flares.
• COL4A3 variants should not preclude immunosuppressive therapy in cIgAN, even if typically associated with Alport syndrome.
• Identifying pathogenic COL4A3 variants can aid in stratifying cIgAN severity beyond the Oxford classification.