Age-Related Penetrance of Hereditary Atypical Hemolytic Uremic Syndrome
Article first published online: 12 SEP 2011
© 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London
Annals of Human Genetics
Volume 75, Issue 6, pages 639–647, November 2011
How to Cite
Sullivan, M., Rybicki, L. A., Winter, A., Hoffmann, M. M., Reiermann, S., Linke, H., Arbeiter, K., Patzer, L., Budde, K., Hoppe, B., Zeier, M., Lhotta, K., Bock, A., Wiech, T., Gaspert, A., Fehr, T., Woznowski, M., Berisha, G., Malinoc, A., Goek, O.-N., Eng, C. and Neumann, H. P. (2011), Age-Related Penetrance of Hereditary Atypical Hemolytic Uremic Syndrome. Annals of Human Genetics, 75: 639–647. doi: 10.1111/j.1469-1809.2011.00671.x
- Issue published online: 4 OCT 2011
- Article first published online: 12 SEP 2011
- Received: 23 March 2011, Accepted: 18 July 2011
- Hemolytic uremic syndrome;
- complement factor H (CFH);
- complement factor I (CFI);
- membrane cofactor protein (MPC);
- age-related penetrance estimations
Hereditary atypical hemolytic uremic syndrome (aHUS), a dramatic disease frequently leading to dialysis, is associated with germline mutations of the CFH, CD46, or CFI genes. After identification of the mutation in an affected aHUS patient, single-site gene testing of relatives is the preventive care perspective. However, clinical data for family counselling are scarce.
From the German-Speaking-Countries-aHUS-Registry, 33 index patients with mutations were approached for permission to offer relatives screening for their family-specific mutations and to obtain demographic and clinical data. Mutation screening was performed using direct sequencing. Age-adjusted penetrance of aHUS was calculated for each gene in index cases and in mutation-positive relatives.
Sixty-one relatives comprising 41 parents and 20 other relatives were enrolled and mutations detected in 31/61. In total, 40 research participants had germline mutations in CFH, 19 in CD46 and in 6 CFI. Penetrance at age 40 was markedly reduced in mutation-positive relatives compared to index patients overall with 10% versus 67% (P < 0.001); 6% vs. 67% (P < 0.001) in CFH mutation carriers and 21% vs. 70% (P= 0.003) in CD46 mutation carriers.
Age-adjusted penetrance for hereditary aHUS is important to understand the disease, and if replicated in the future, for genetic counselling.