Age-Related Penetrance of Hereditary Atypical Hemolytic Uremic Syndrome

Abstract

SummaryHereditary 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.

Genetics and Outcome of Atypical Hemolytic Uremic Syndrome

“…Between 2000 and 2008, the mean number of patients referred each year at the time of the first episode of aHUS was 15 (range, [8][9][10][11][12][13][14][15][16][17][18][19][20][21], suggesting that the annual incidence of aHUS is at least 0.23/year per 10 6 people in the French population.…”

“…The genetic screening of patients with aHUS from national or international registries has provided an estimation of the frequency of mutations in the complement genes (9)(10)(11)(12). In contrast, our knowledge of the presentation and outcome of aHUS derives from only a few series (9,13,14).…”

Factors determining penetrance in familial atypical haemolytic uraemic syndrome

“…Sullivan et al studied affected individuals and their relatives. The penetrance in 18 affected index cases with a CFH mutation was 67% by the age of 40 years and 100% by the age of 65 years 25. Two of the index cases had a further family member who was affected by the disease and both were found to carry the same CFH mutation.…”

Dynamics of complement activation in aHUS and how to monitor eculizumab therapy

“…It is well known that the penetrance of aHUS in carriers of complement gene mutations is incomplete, 1,2,4,5,7,27,33,34 and some subjects never develop aHUS or manifest the disease very late in adulthood. An epidemiologic study in familial cases reported that penetrance of aHUS by age 45 years was 50% among carriers of gene mutations.…”