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Project Description

Alport syndrome (AS) is an inherited disorder affecting the type IV collagen of the GBM with prevalence varying from 1 in 5000 to 1 in 53000 of the population [1,2]. While in adults it is the second most common inherited etiology of chronic kidney disease (CKD) and second leading cause of focal segmental glomerulosclerosis (FSGS), in children it is relatively rare [3]. AS occurs due to defect in the α3, α4 and α5 chains of the type IV collagen encoded by the COL4A3, COL4A4 and COL4A5 genes. The combination of α chains forming the triple helix structure α3- α4 -α5 is located in the glomerular basement membrane (GBM), cochlear basement membrane [4]. Any abnormality in each of these α chains disrupts the helix resulting in GBM abnormalities, sensorineural hearing loss (SNHL) and ocular changes such as anterior lenticonus. Clinical spectrum of AS is highly variable in children ranging from isolated microscopic hematuria, proteinuria, nephrotic syndrome, CKD etc. [1,4] Based on the mode of inheritance and pathogenic nature of the COL4A variant AS can be classified as X-linked (XLAS), autosomal recessive (ARAS) and autosomal dominant type of AS (ADAS).  While XLAS accounts for 80% of the AS, 15% is ARAS and 5% accounts for the rare ADAS [2,5]. Molecular diagnosis of AS and interpretation of the pathogenicity of COL4A variant is often a challenge. Standard recommendations have been proposed in the recent era using American College of Medical Genetics (ACMG) criteria to aid in the genetic diagnosis of AS [3,6].