# Analyzing three pedigrees in X-linked Alport syndrome with the presentation of nephrotic syndrome

## TL;DR

This paper reports on three families with X-linked Alport syndrome where nephrotic syndrome was the main symptom, identifying new genetic mutations in the COL4A5 gene.

## Contribution

The study identifies two novel mutations in the COL4A5 gene associated with nephrotic syndrome as a primary clinical manifestation in X-linked Alport syndrome.

## Key findings

- Renal biopsy confirmed X-linked Alport syndrome in probands A and B with nephrotic syndrome as the main phenotype.
- Three novel mutations in the COL4A5 gene were identified, leading to shortened proteins and potential pathogenic effects.
- Proband C and his mother progressed to end-stage renal disease, highlighting the severity of the identified mutations.

## Abstract

Alport syndrome (AS) is a common cause of end-stage renal disease (ESRD) with various clinical symptoms and incomplete manifestation. Patients with AS and other renal disorders are often misdiagnosed. This study reported three X-linked dominant Alport syndrome (XLAS) pedigrees with nephrotic syndrome (NS) as the predominant phenotype and analyzed COL4A5 gene alterations.

Three Han Chinese XLAS pedigrees were recruited, and clinical phenotypes were obtained. The pre-certified individuals’ peripheral blood DNA was taken, and whole-genome next-generation sequencing (NGS) was performed for candidate genes and mutation screening, followed by NGS or Sanger sequencing of suspected mutant types in participating family members.

Both probands A and B were diagnosed with NS through biochemical tests, and X-linked Alport syndrome-associated renal injury was diagnosed by renal biopsy. The biopsy revealed focal foamy cells in the renal interstitium, tearing and delamination changes in the glomerular basement membrane, and negative α3 and α5 chains of type IV collagen. Proband C, who was earlier diagnosed with NS, has now advanced to ESRD, along with his mother and proband A’s mother. Genetic sequencing of all three pedigrees identified three mutations, namely, c.5020C>T, c.4435_4445del, and c.1584_1587+6del in the X-linked dominant gene COL4A5 (NM_000495.5). These mutations lead to the production of shortened proteins, potentially impacting the function of COL4A5 and causing pathogenic effects.

The novel c.4435_4445del and c.1584_1587+6del mutations not only enrich the spectrum of mutations in the COL4A5 gene but also indicate that carriers of both mutation sites and those with mutation c.5020C>T may present NS as their primary clinical manifestation.