This adolescent female patient experienced nephrotic-range proteinuria, hypoalbuminaemia, hypertension and haematuria. These findings are consistent with a mixed nephrotic-nephritic picture with a broad differential diagnosis. The differential includes, but is not limited to glomerulosclerosis, post-infectious glomerulonephritis, lupus nephritis and other causes of nephrotic/nephritic syndromes. Complement levels and vasculitis screening yielded no abnormal findings. Viral serology and anti-streptolysin titres were normal, making an infectious aetiology unlikely. Abdominal ultrasound, lactate dehydrogenase and urate were all normal, thus making a malignant cause unlikely. The patient had no recent medication or toxin exposure.

Biopsy showed marked effacement of the epithelial cell foot processes. There was some irregularity to the epithelial side of the basement membrane, but no other structural abnormalities were identified. These findings were in keeping with a diagnosis of focal segmental glomerulosclerosis, and as such, genetic studies for steroid-resistant nephrotic syndrome were performed. Immunofluorescence showed no evidence of an immune complex deposition disease process, thus excluding diagnoses such as IgA nephropathy, C3 glomerulopathy, lupus nephritis, etc. Electron microscopy revealed marked foot process effacement, consistent with a diffuse podocytopathy (Fig. 1A–D).

The selected steroid-resistant nephrotic syndrome genetic panel targeted 69 different genes using a custom designed SureSelect Target Enrichment System kit, with next-generation sequencing using a MiSeq (Illumina) analyser. Genetic studies on the patient revealed a heterozygous, likely pathogenic variant in the COL4A5 gene – c.3722G > A, p.(Gly1241Asp). At the time of presentation, this variant had not been reported in the literature. The c.3722G > A sequence change is predicted to cause the substitution of a highly conserved glycine residue for an aspartic acid residue at position 1241. Other amino acid changes at the same position have been reported in the literature in association with X-linked Alport syndrome: p.(Gly1241Arg), p(Gly1241Cys), and p.(Gly1241Val) [1, 2]. This was suggestive of a diagnosis of X-linked Alport syndrome. Parental genetics were performed, both of which were negative, suggesting that this variant arose de novo in this patient, supporting its pathogenicity.

Following the diagnosis of X-linked Alport syndrome, the patient’s immunosuppression was stopped and she was commenced on an angiotensin receptor blocker. Given the normal parental genetics, the likelihood of our patient’s siblings being affected was low; however, the risk of gonadal mosaicism could not be fully excluded. As such, urinalysis and blood pressures were taken on all first-degree relatives, all of which were normal. She was transitioned to adult services with normal hearing and eye examinations.