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Autosomal Dominant Alport COL4A3 — ESENeph MCQ

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HardGlomerulonephritisAutosomal Dominant Alport COL4A3ESENeph

A 52-year-old man presents with bilateral hearing loss, progressive CKD (eGFR 35 mL/min/1.73m2), and a maternal uncle who died of kidney failure. His mother has mild CKD. Urine shows persistent microscopic haematuria with proteinuria. Renal biopsy EM shows irregular thinning and thickening of the GBM with lamellation. Genetic testing reveals a COL4A3 variant. What is the inheritance pattern of his form of Alport syndrome?

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Correct answer: D — Autosomal dominant

COL4A3 mutations can cause either autosomal recessive Alport syndrome (biallelic mutations — severe, childhood-onset) or autosomal dominant Alport syndrome (heterozygous mutation — milder, adult-onset). This patient has adult-onset progressive disease with a maternal uncle affected and mother with mild CKD — consistent with autosomal dominant inheritance through COL4A3 or COL4A4 (both encoding type IV collagen alpha chains on chromosome 2). Autosomal dominant Alport accounts for ~15-20% of cases and is increasingly recognised with genetic testing. It was previously classified as 'thin basement membrane disease' or 'benign familial haematuria' — now understood to be a milder form of Alport. X-linked Alport involves COL4A5.

Reference: Kashtan et al 2018 – Alport Syndrome Revised Classification; KDIGO 2021 – Glomerular Diseases