# Coexisting genetic kidney disease explains many cases of ‘familial’ IgA nephropathy where the proband has biopsy-confirmed mesangial IgA deposits

## TL;DR

This study finds that many cases of familial IgA nephropathy are actually due to a coexisting genetic kidney disease, not just IgA nephropathy alone.

## Contribution

The study shows that genetic kidney disease often coexists with IgA nephropathy in families, explaining some cases previously labeled as purely familial.

## Key findings

- 45% to 82% of families with familial IgA nephropathy had genetic kidney disease variants.
- Some probands lacked the genetic variant found in affected family members.
- Two sporadic IgA nephropathy cases also had genetic kidney disease variants.

## Abstract

One in seven people with IgA nephropathy has another apparently-affected family member. This study examined how often biopsy-proven familial and sporadic IgA nephropathy were associated with genetic kidney disease.

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 of 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.

Nine of the 11 probands (82%) with familial nephropathy and 30 of those with sporadic disease (77%) had kidney failure. At least five (45%) and possibly nine (82%) of the 11 families studied had disease-associated heterozygous variants consistent with a coexistent genetic kidney disease (autosomal dominant (AD) and X-linked (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 X-linked. Sometimes the proband with IgA nephropathy did not have the genetic variant found in other apparently-affected family members. Sometimes two genetic variants corresponding to two different diseases were present in the same family. Two of the 39 people with sporadic IgA nephropathy (5%) also had disease-causing variants consistent with genetic kidney disease (AD Alport syndrome, cystinuria).

Many familial cases of IgA nephropathy result from mesangial IgA deposition in the setting of 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.