ORIGINAL RESEARCH article
Front. Med.
Sec. Nephrology
Coexisting genetic kidney disease explains many cases of 'familial' IgA nephropathy where the proband has biopsy-confirmed mesangial IgA deposits
Yuxin Li 1
Jing Zhang 1
Zhuo Yin 1
Zoe Zhou 1
Bocheng Huang 1
Khalid Mahmood 1
Deb Colville 1
David Barit 1
Russell Auwardt 2
Rob Fassett 3
Kathy Paizis 1
Francesco Ierino 1
Timothy Pianta 1
David Langsford 1
Mary Huang 1
Judy Savige 1
1. The University of Melbourne, Parkville, Australia
2. Albury Wodonga Health Albury Campus, Albury, Australia
3. Tasmania Department of Health, Hobart, Australia
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Abstract
Background: One in 7 people with IgA nephropathy have another apparently-affected family member. This study examined how often biopsy-proven familial and sporadic IgA nephropathy were associated with coexistent genetic kidney disease. Methods: Eleven unrelated people with biopsy-proven IgA nephropathy and another family member with kidney tests compatible with IgA nephropathy were recruited. All available family members were assessed for genetic kidney disease, using Whole Exome Sequencing (WES). Their results were compared with those from 39 people with sporadic IgA nephropathy. All sequencing results were filtered for pathogenic variants in genes associated with genetic kidney disease (Genomics England panels, n=384). Variants were assessed for pathogenicity using ClinVar and the ACMG/AMP criteria in Alamut. Results: Nine of the 11 probands (82%) with familial nephropathy and 30 of those with sporadic disease (77%) had kidney failure. At least 5 (45%) and possibly 9 (82%) of the 11 families studied had disease-associated heterozygous variants consistent with a coexistent genetic kidney disease (autosomal dominant (AD) and Xlinked (XL) Alport syndrome, ADTKD-HNF1B, and possibly Dent disease, Focal and Segmental Glomerulosclerosis (FSGS) and CHARGE syndrome). Inheritance for all these diseases was AD or XLinked. Sometimes the proband with IgA nephropathy did not have the genetic variant found in other apparently-affected family members (Family 3F, 11B). Sometimes two genetic variants corresponding to two different diseases were present in one family (Family 3F). Two of the 39 people with sporadic IgA nephropathy (5%) also had disease-causing variants consistent with genetic kidney disease (AD Alport syndrome, Cystinuria). Conclusions: Many familial cases of IgA nephropathy result from mesangial IgA deposition in coexisting genetic kidney disease. Sometimes genetic kidney disease is not detected in the proband but is present in another family member. Individuals from families with IgA nephropathy should be offered genetic testing.
Summary
Keywords
Alport syndrome, Autosomal dominant Alport syndrome, familial haematuria, Familial hematuria, Familial kidney disease, genetic kidney disease, IgA nephropathy, severe IgA nephropathy
Received
16 June 2025
Accepted
29 December 2025
Copyright
© 2025 Li, Zhang, Yin, Zhou, Huang, Mahmood, Colville, Barit, Auwardt, Fassett, Paizis, Ierino, Pianta, Langsford, Huang and Savige. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhuo Yin; Judy Savige
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