Risk of atypical HUS among family members of patients carrying complement regulatory gene abnormality.

Abstract Introduction Atypical hemolytic uremic syndrome (aHUS) is mainly due to complement regulatory gene abnormalities with a dominant pattern but incomplete penetrance. Thus, healthy carriers can be identified in any family of aHUS patients, but it is unpredictable if they will eventually develop aHUS. Methods Patients are screened for 10 complement regulatory gene abnormalities and once a genetic alteration is identified, the search is extended to at-risk family members. The present cohort study includes 257 subjects from 71 families: 99 aHUS patients (71 index cases + 28 affected family members) and 158 healthy relatives with a documented complement gene abnormality. Results Fourteen families (19.7%) experienced multiple cases. Over a cumulative observation period of 7 595 person-years, only 28 family members carrying gene mutations experienced aHUS (overall penetrance of 20%) leading to a disease rate of 3.69 events for 1 000 person-years. The disease rate was 7.47 per 1 000 person-year among siblings, 6.29 among offspring , 2.01 among parents, 1.84 among carriers of variants of uncertain significance and 4.43 among carriers of causative variants. Conclusions The penetrance of aHUS seems a lot lower than previously reported. Moreover, the disease risk is higher in carriers of causative variants and is not equally distributed among generations: siblings and the offspring of patients have a much greater disease risk than parents. However, risk calculation may depend on variant classification that could change over time.