A 25-year-old man with hematuria and sensorineural deafness has a renal biopsy showing irregular thinning and splitting of the GBM with a 'basket-weave' pattern on electron microscopy. His mother has microscopic hematuria but no renal failure. COL4A5 mutation is found. What is the inheritance pattern and expected prognosis?

• A Autosomal recessive (COL4A3 or COL4A4 mutation); severe disease in homozygotes
• B X-linked (COL4A5 mutation); males progress to ESRD by age 20–30, females are carriers with variable hematuria ✓
• C Autosomal dominant (COL4A3 mutation); ESRD occurs equally in males and females by middle age
• D De novo mutation; no family history expected; prognosis unpredictable

Explanation

Alport syndrome due to COL4A5 mutation (encoding the alpha-5 chain of type IV collagen) is X-linked and accounts for ~80% of Alport syndrome cases. Affected males lack functional alpha-5 chain, resulting in defective alpha-3/alpha-4/alpha-5 collagen IV trimer in GBM, lens capsule, and cochlea — causing nephritis, sensorineural deafness, and anterior lenticonus. Males develop ESRD before age 30; females (heterozygous) usually have only microscopic hematuria but ~15% develop renal impairment. Autosomal forms result from COL4A3/COL4A4 mutations affecting alpha-3 or alpha-4 chains.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.