title: A COL4A5 mutation with glomerular disease and signs of chronic thrombotic microangiopathy.
abstract: COL4A5 mutations are a known cause of Alport syndrome, which typically manifests with haematuria, hearing loss and ocular symptoms. Here we report on a 16-year-old male patient with a negative family history who presented with proteinuria, progressive renal failure and haemolysis, but without overt haematuria or hearing loss. A renal biopsy revealed features of atypical IgA nephropathy, while a second biopsy a year later showed features of focal segmental glomerulosclerosis, but was finally diagnosed as chronic thrombotic microangiopathy. Targeted sequencing of candidate genes for steroid-resistant nephrotic syndrome and congenital thrombotic microangiopathy was negative. Despite all therapeutic efforts, including angiotensin-converting enzyme inhibition, immunosuppressive therapy, plasma exchanges and rituximab, the patient progressed to end-stage renal disease. When a male cousin presented with nephrotic syndrome years later, whole-exome sequencing identified a shared disruptive COL4A5 mutation (p.F222C) that showed X-linked segregation. Thus, mutations in COL4A5 give rise to a broader spectrum of clinical presentation than commonly suspected, highlighting the benefits of comprehensive rather than candidate genetic testing in young patients with otherwise unexplained glomerular disease. Our results are in line with an increasing number of atypical presentations of single-gene disorders identified through genome-wide sequencing.
authors.affiliation: Renal Division, Department of Internal Medicine , Medical Center - University of Freiburg , Freiburg , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wuttke
authors.affiliation: Institute for Surgical Pathology , Medical Center - University of Freiburg , Freiburg , Germany ; Center for Chronic Immunodeficiency (CCI) , Medical Center - University of Freiburg , Freiburg , Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Seidl
authors.affiliation: Renal Division, Department of Internal Medicine , Medical Center - University of Freiburg , Freiburg , Germany.
authors.forename: Angelica
authors.initials: A
authors.lastname: Malinoc
authors.affiliation: Nephrology, 4th Department of Internal Medicine , Klinikum Wels-Grieskirchen , Wels , Austria.
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Prischl
authors.affiliation: Renal Division, Department of Internal Medicine , Medical Center - University of Freiburg , Freiburg , Germany.
authors.forename: E Wolfgang
authors.initials: EW
authors.lastname: Kuehn
authors.affiliation: Renal Division, Department of Internal Medicine , Medical Center - University of Freiburg , Freiburg , Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.affiliation: Renal Division, Department of Internal Medicine , Medical Center - University of Freiburg , Freiburg , Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
keywords: Alport; FSGS; IgA nephropathy; nephrotic syndrome; thrombotic microangiopathy