Spectrum of Alport syndrome in an Indian cohort.

ABSTRACT

BACKGROUND: Next-generation sequencing has enabled non-invasive diagnosis of type IV collagen disease in clinical settings other than the typical presentation of Alport syndrome (AS). METHODS: We reviewed the clinical and histological records of children diagnosed with Alport syndrome based on next-generation sequencing. Variants on clinical exome sequencing were categorized using ACMG 2015 criteria. RESULTS: During 2015-2023, we found 43 patients (34 boys) with 39 variants in COL4A5 (n = 27), COL4A4 (n = 7), and COL4A3 (n = 5). Thirty, 8, and 5 patients had X-linked, autosomal recessive, and autosomal dominant disease, respectively. The median (IQR) age and eGFR at diagnosis were 10 (7-13) years and 100.1 (59-140) ml/min/1.73 m2, respectively. Fifteen patients were initially diagnosed with steroid-resistant nephrotic syndrome. Alport syndrome was suspected in these patients due to persistent microscopic hematuria, eGFR < 90 ml/min/1.73 m2, characteristic histology, and/or non-response to immunosuppression. Of 26 patients who underwent kidney biopsy, light microscopy revealed focal segmental glomerulosclerosis, minimal change disease, and mesangial proliferative glomerulonephritis in 9, 9, and 8 patients, respectively. Electron microscopy (n = 18) showed characteristic glomerular basement membrane changes and/or foot process effacement in 12 and 16 cases, respectively. Twenty-one patients (48.8%) had high-frequency sensorineural hearing loss, while two had lenticonus. Twelve patients progressed to chronic kidney disease stages 4-5. Median survival (IQR) with eGFR > 30 ml/min/1.73 m2 was 15.6 (13-18) years. CONCLUSIONS: The phenotype of Alport syndrome varies from asymptomatic urinary abnormalities to hematuria, proteinuria and/or low eGFR, and steroid-resistant nephrotic syndrome. Adverse outcomes are common, especially in boys with X-linked disease.