Rare Collagenous Heterozygote Variants in Children With IgA Nephropathy

Abstract

Introduction: Childhood IgA nephropathy (cIgAN) is a primary glomerulonephritis clinically characterized by microscopic hematuria and proteinuria, the presence of which may potentially overlap with Alport syndrome. Interestingly, earlier studies suggested that familial IgAN could be linked to the chromosome 2q36 region, also the coding region for collagen type 4 alpha 3/4 (COL4A3/A4). Methods: To investigate a possible relationship or phenocopy between Alport syndrome and cIgAN, COL4A3, COL4A4, and COL4A5 exons were sequenced in 36 cIgAN patients. Clinical data and treatment were collected retrospectively. COL4A3/A4/A5 variants were classified according to American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Results: Four of 36 cIgAN patients were affected by ACMG class 4/5 COL4A3 heterozygous variants (COL4A3-cIgAN). We found no COL4A4 or COL4A5 variant. Despite having rare and deleterious COL4A3 variants, 3 of 4 COL4A3-cIgAN children developed clinical and biologic features of active IgAN rather than Alport syndrome. Response to intensive immunosuppressive treatment was favorable, leading to a reduction of endocapillary and extracapillary proliferation lesions. High levels of immune immunoglobulin G and A (IgG/IgA) complexes, reduction of proteinuria, and gradual stabilization of estimated glomerular filtration rate (eGFR) argued against Alport syndrome. Nevertheless, COL4A3-cIgAN patients seemed predisposed to a more serious IgAN presentation compared with the non-COL4A3-cIgAN group, with more glomerulosclerosis and a lower eGFR over time. One of the 4 patients underwent kidney transplant with subsequent IgAN recurrence. Conclusions: Predisposition factors for developing serious cIgAN f Q4 lare-up should be considered for cIgAN with COL4A3 pathologic heterozygous variants. COL4A3 variants, usually responsible for Alport syndrome in adults, should not automatically exclude an immunosuppressive regimen in cIgAN. Moreover, evidence of an ACMG class 4/5 COL4A3 variant in early-stage cIgAN could be a helpful tool for stratifying severity of cIgAN beyond the Oxford classification.

The 2019 and 2021 International Workshops on Alport Syndrome

“…The presence of a glomerular disease (primary membranoproliferative GN/C3 glomerulopathy, IgA nephropathy) does not exclude AS [ 16 , 36 , 37 ]. The association between AS and immune glomerular diseases suggest that the abnormal GBM resulting from the presence of pathogenic COL4A3/A4/A5 variants may predispose to immune-mediated injury.…”

Case Report: Unusual Aggregation of Different Glomerulopathies in a Family Resolved by Genetic Testing and Reverse Phenotyping

“…We and others reported that up to 10% of patients with diagnosis of familial FSGS have pathogenic variants in one of the COL4A genes; subsequent large studies showed that COL4A variants are the most common cause of CKD of unknown etiology in adults (6)(7)(8). Two studies also found pathogenic variants in COL4A3, COL4A4, and COL4A5 in 10-20% of patients with presumed IgA nephropathy (9,10). One approach that investigators have used to ensure accurate diagnosis of kidney disease after genetic testing is by performing reverse phenotyping after genetic testing.…”

“…Even when genetic etiology is established, there is considerable overlap between different GDs. For example it has been reported that up to 10% of classical hereditary podocytopathies (focal and segmental glomerulosclerosis) are due to pathogenic variants in COL4A genes, and pathogenic variants in these same genes have also been reported in patients with presumed IgA nephropathy (6)(7)(8)(9)(10). This reported phenotypic pleiotropy in genes associated with GD emphasizes the importance of genetic diagnosis and careful scrutiny of phenotype data after genetic diagnosis to ensure accurate disease classification (10).…”

“…For example it has been reported that up to 10% of classical hereditary podocytopathies (focal and segmental glomerulosclerosis) are due to pathogenic variants in COL4A genes, and pathogenic variants in these same genes have also been reported in patients with presumed IgA nephropathy (6)(7)(8)(9)(10). This reported phenotypic pleiotropy in genes associated with GD emphasizes the importance of genetic diagnosis and careful scrutiny of phenotype data after genetic diagnosis to ensure accurate disease classification (10). In this report, we describe a family with unusual aggregation of different GDs that was clearly defined by a combination of genetic diagnosis and careful reverse phenotyping.…”

Identification of COL4A4 variants in Chinese patients with familial hematuria

“…Usually, from clinical phenotype and renal biopsy, the coexistence of AS and IgA nephropathy is attributed to two independent causes. However, some variants in the COL4A3, COL4A4, or COL4A5 gene seem to increase the susceptibility to IgA nephropathy, which is supported by IgA deposits occasionally observed in the AS patients and the COL4A3, COL4A4, or COL4A5 gene variants reported in a minority of IgA nephropathy patients (Kamiyoshi et al, 2016;Li et al, 2020;Cambier et al, 2021). Based on the identified responsible variant, COL4A4-associated nephropathies, a sub-classification of the conditions in the two pedigrees, is strongly recommended.…”