Type IV Collagen Mutations in Familial IgA Nephropathy

Li, Yifu; Groopman, Emily; D’Agati, Vivette D.; Prakash, Sindhuri; Zhang, Junying; Mizerska-Wasiak, Małgorzata; Çalışkan, Yaşar; Fasel, David; Karnib, Hussein H.; Bono, Luisa; Omran, Sadek A.Ai.; Sabban, Essam Ai.; Kiryluk, Krzysztof; Caridi, Gianluca; Ghiggeri, Gian Marco; Sanna‐Cherchi, Simone; Scolari, Francesco; Gharavi, Ali G.

doi:10.1016/j.ekir.2020.04.011

Cited by 33 publications

(29 citation statements)

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“…To date, no single causal genes have yet been identified in familial IgA cases, suggesting that the disease is multifactorial or has a complex trait, where one or more genes are implicated in combination with environmental factors [ 3 , 4 , 19 ]. A considerable portion of missing heritability so far reported in GWAS could be explained by multiple rare variants [ 17 , 20 – 22 ]. Recent studies with exome analysis revealed certain familial or sporadic IgAN harbor variants in known renal disease-causing genes, suggesting that IgAN may be driven or modified by genes of other familial renal disorders [ 17 , 20 – 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…A considerable portion of missing heritability so far reported in GWAS could be explained by multiple rare variants [ 17 , 20 – 22 ]. Recent studies with exome analysis revealed certain familial or sporadic IgAN harbor variants in known renal disease-causing genes, suggesting that IgAN may be driven or modified by genes of other familial renal disorders [ 17 , 20 – 22 ]. Thus, next generation sequencing will help improve our understanding of genes implicated in the pathogenesis of IgAN.…”

Section: Discussionmentioning

confidence: 99%

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Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

et al. 2021

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Background IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although most IgAN cases are sporadic, few show a familial aggregation. However, the prevalence and prognosis of IgAN individuals with positive familial history (FH) of renal disorders remains uncertain. To address these issues, we conducted a longitudinal observational study on a single-institution cohort of patients with biopsy-proven IgAN. Methods A total of 467 IgAN patients who underwent renal biopsy during 1994 to 2019 were ascertained to have positive- or negative-FH by history taking and were followed for an average of 8.9 years. We compared the clinical and pathological features of the two subgroups. The primary outcome, a composite of a hard endpoint (end-stage renal disease [ESRD]) and surrogate endpoint (a 50% or more reduction in the estimated glomerular filtration rate [eGFR] from baseline), was evaluated. To estimate the risk for progression to ESRD, a Cox proportional hazards analysis was performed for a subset of patients who underwent follow-up for > 2 years and had an eGFR > 30 mL/min/1.73 m2 at baseline (n = 389; observation, 8.7 years). Results Positive-FH subtype accounted for 11.6% (n = 54) of all IgAN patients. At baseline, there were no significant differences between the positive- and negative-FH subgroups regarding age, sex, comorbid disease, MEST-C score, observation period, and therapeutic interventions. However, the eGFR value at baselines was significantly lower in the positive-FH subgroup than in the negative-FH subgroup (P < 0.01). On multivariate analysis, positive-FH emerged an independent determinant of poorer renal outcomes (odds ratio, 2.31; 95% confidence interval, 1.10–4.85; P = 0.03), after adjusting for confounding factors. eGFR at follow-up was significantly lower in the positive-FH subgroup than in the negative-FH subgroup after adjustment for age and observation period. Conclusions Positive-FH was found in 11.6% of all IgAN patients, consistent with the incidence seen in previous literature. A significantly lower eGFR at baseline and last follow-up and unfavorable renal outcomes in the positive-FH subgroup suggest that certain genetic risk factors predisposing to renal failure may exist in a fraction of our IgAN cohort. (331 words).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

et al. 2021

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“…Recently, a type IV collagen mutation was described in adult familial IgAN, suggesting a possible Alport family with IgA deposits. 30 Unfortunately, a detailed histopathology was not available for the families reported in the study. Interestingly, as far back as 1995, Berthoux et al also described an IgAN cohort, which showed a notable proportion (40%) of patients with a thin glomerular membrane, indicating either a specific subgroup (with an unfavorable prognosis) or an association with thin membrane nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rare Collagenous Heterozygote Variants in Children With IgA Nephropathy

Cambier

Robert

Hogan

et al. 2021

Kidney International Reports

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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.

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“…Individuals with IgA glomerulonephritis and concomitant thin basement membrane nephropathy or X-linked Alport syndrome are not uncommon [38][39][40][41][42][43] . Up to 20% of families with IgA glomerulonephritis have a pathogenic COL4A3 or COL4A4, or less often, a COL4A5 variant [45][46][47] . IgA glomerulonephritis appears to occur independent of variant type, such as truncating or missense change.…”

Section: Iga Glomerulonephritismentioning

confidence: 99%

Pathogenic Variants in the Genes Affected in Alport Syndrome (COL4A3–COL4A5) and Their Association With Other Kidney Conditions: A Review

Savige

Harraka

2021

American Journal of Kidney Diseases

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Type IV Collagen Mutations in Familial IgA Nephropathy

Cited by 33 publications

References 8 publications

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study

Rare Collagenous Heterozygote Variants in Children With IgA Nephropathy

Pathogenic Variants in the Genes Affected in Alport Syndrome (COL4A3–COL4A5) and Their Association With Other Kidney Conditions: A Review

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