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Phenotypes
Original article
Factors determining penetrance in familial atypical haemolytic uraemic syndrome
  1. Francis H Sansbury1,2,3,
  2. Heather J Cordell4,
  3. Coralie Bingham2,5,
  4. Gilly Bromilow1,
  5. Anthony Nicholls5,
  6. Roy Powell6,
  7. Bev Shields2,
  8. Lucy Smyth5,
  9. Paul Warwicker7,
  10. Lisa Strain8,
  11. Valerie Wilson8,
  12. Judith A Goodship4,
  13. Timothy H J Goodship4,
  14. Peter D Turnpenny1,2
  1. 1Peninsula Clinical Genetics Service, Royal Devon & Exeter NHS Foundation Trust, Royal Devon & Exeter Hospital (Heavitree), Exeter, UK
  2. 2University of Exeter Medical School, University of Exeter, Exeter, UK
  3. 3Bristol Clinical Genetics Service, University Hospitals Bristol NHS Foundation Trust, Clinical Genetics, St. Michael's Hospital, Bristol, UK
  4. 4Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  5. 5Department of Renal Medicine, Royal Devon & Exeter NHS Foundation Trust, Royal Devon & Exeter Hospital (Wonford), Exeter, UK
  6. 6Research Design Service South West, Royal Devon & Exeter NHS Foundation Trust, Royal Devon & Exeter Hospital (Wonford), Exeter, UK
  7. 7Lister Renal Units, East and North Hertfordshire NHS Trust, Stevenage, UK
  8. 8Northern Molecular Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  1. Correspondence to Professor Tim Goodship, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; t.h.j.goodship{at}ncl.ac.uk

Abstract

Background Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.3643C>G; p. Arg1215Gly) in whom a common lineage is probable. 25 individuals have been affected with aHUS with three peaks of incidence—early childhood (n=6), early adulthood (n=11) and late adulthood (n=8). Eighteen individuals who have not developed aHUS carry the mutation.

Methods We estimated penetrance at the ages of 4, 27, 60 and 70 years as both a binary and a survival trait using MLINK and Mendel. We genotyped susceptibility factors in CFH, CD46 and CFHR1 in affected and unaffected carriers.

Results and Conclusions We found that the estimates of penetrance at the age of 4 years ranged from <0.01 to 0.10, at the age of 27 years from 0.16 to 0.29, at the age of 60 years from 0.39 to 0.51 and at the age of 70 years from 0.44 to 0.64. We found that the CFH haplotype on the allele not carrying the CFH mutation had a significant effect on disease penetrance. In this family, we did not find that the CD46 haplotypes had a significant effect on penetrance.

  • Renal Medicine
  • Clinical genetics

https://doi.org/10.1136/jmedgenet-2014-102498

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