GENOTYPIC-PHENOTYPIC SPECTRUM OF COL4 MUTATION & TRANSPLANT OUTCOME OF ALPORT SYNDROME: A SINGLE CENTRE EXPERIENCE

Introduction:

Alport syndrome is an inherited kidney disorder characterized by hematuria, renal failure, hearing loss, and ocular abnormalities. Pathogenic variants in the genes COL4A3, COL4A4, or COL4A5 lead to a range of clinical manifestations. Studies indicate that autosomal recessive inheritance and males with X-linked Alport syndrome often have more severe disease, while autosomal dominant inheritance and females with X-linked Alport syndrome show greater variability in disease severity. Renal transplant recipients with Alport syndrome typically exhibit patient and graft survival rates comparable to or better than those with other renal diseases.

Methods:

This retrospective observational analysis at a single center involved 14 patients diagnosed with Alport syndrome. The study aimed to explore genotypic-phenotypic correlations and transplant outcomes. Clinical, genetic, laboratory, and pathological data were collected and analyzed. Diagnosis was confirmed through genetic testing in 12 patients, electron microscopy of a renal biopsy in one patient, and clinical criteria in another.

Results:

The study identified 11 distinct mutations (in 12 patients), seven of which were previously unreported in the literature. These mutations affected different type IV collagen α chains, with the distribution being COL4A4 (46%), COL4A5 (36%), and COL4A3 (18%). Of these, 3 (27%) were classified as pathogenic, and another 3 (27%) were likely pathogenic variant.

Nephrotic syndrome was the most common clinical presentation, observed in 8 (57%) patients, all with histologically confirmed focal segmental glomerulosclerosis (FSGS).Approximately one-third of patients exhibited extrarenal manifestations such as hearing loss and ocular abnormalities.

At the time of referral, 35% of the patients had progressed to end-stage renal disease (ESRD), suggesting a late diagnosis or rapid disease progression. One additional patient developed ESRD during follow-up, underscoring the progressive nature of the disease. A family history of kidney disease was noted in 4 (28.5%) patients, highlighting the hereditary nature of the disorder.

Two patients underwent renal transplantation—one received a kidney from a living-related donor (mother), and the other from a deceased donor. Both patients showed excellent graft survival and renal function after two-years of follow-up, with no evidence of anti-glomerular basement membrane (anti-GBM) disease.

Conclusions:

This study highlights the significant variability in the clinical and genetic presentation of Alport syndrome. Patients with COL4A4 mutations and missense mutations generally had better renal survival, suggesting these mutations may lead to a less aggressive disease course. Conversely, individuals with COL4A3 mutations and those presenting with hearing loss had poorer renal outcomes, supporting the idea that specific genotypes may predispose patients to more severe phenotypes.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.