Table 1.

Recommendations for genetic testing for Alport syndrome.

Clinical spectrum

The typical clinical features of Alport syndrome are persistent haematuria, sometimes with progressive renal failure, together with a family history of haematuria or renal failure. Proteinuria, a hearing loss or a lamellated or thinned glomerular basement membrane may be present. Other phenotypes associated with pathogenic variants in the COL4A3–COL4A5 genes and hence Alport syndrome include persistent proteinuria, steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis (FSGS); familial IgA glomerulonephritis; and end-stage kidney failure of unknown cause. Pathogenic COL4A3–COL4A5 variants are the commonest genetic abnormality found in all these phenotypes.

Genetic testing

The most accurate test for the detection of a causative pathogenic variant in the COL4A3–COL4A5 genes is comprehensive parallel genetic testing of the entire coding sequences of all three COL4A5, COL4A3 and COL4A4 genes. Where Alport syndrome is suspected, genetic testing for diagnosis should take precedence over even a renal biopsy. Where a causative variant is demonstrated, a renal biopsy may not be necessary. The COL4A3–COL4A5 genes should also be included in multigene Massively Parallel Sequencing renal disease panels for the extended Alport phenotypes. The Alport syndrome-specific modifications of the ACMG standards and guidelines for the Interpretation of Sequence Variants apply.