TY - JOUR
T1 - Risk of Atypical HUS Among Family Members of Patients Carrying Complement Regulatory Gene Abnormality
AU - Ardissino, Gianluigi
AU - Longhi, Selena
AU - Porcaro, Luigi
AU - Pintarelli, Giulia
AU - Strumbo, Bice
AU - Capone, Valentina
AU - Cresseri, Donata
AU - Loffredo, Giulia
AU - Tel, Francesca
AU - Salardi, Stefania
AU - Sgarbanti, Martina
AU - Martelli, Laura
AU - Rodrigues, Evangeline Millicent
AU - Borsa-Ghiringhelli, Nicolò
AU - Montini, Giovanni
AU - Seia, Manuela
AU - Cugno, Massimo
AU - Carfagna, Fabio
AU - Consonni, Dario
AU - Tedeschi, Silvana
N1 - Funding Information:
We are thankful to ?Progetto Alice ONLUS. Associazione per la Lotta alla SEU? for their continuous and precious support. We also want to thank the following physicians (members of the ItalKId-HUS Network) for their dedication to our and their patients and for their precious collaboration and commitment toward our center that has been essential to perform the present analysis: Andrea Airoldi (Novara), Karen Amar (Cernusco SN), Andrea Artoni (Milano), Alice Atzeni (Cagliari), Bruno Basolo (Torino), Teresa Bencivenga (Aversa), Maria Ester Bernardo (Milano), Elena Bezze (Alessandria), Maurizio Brigante (Campobasso), Alessandro Bucalossi (Siena), Valeria Calbi (Milano), Aldo Casani (Massa Carrara), Alessandro Castiglioni (Busto Arsizio), Francesco Catalano (Reggio Calabria), Luigia Costantini (Vercelli), Calogero Cirami (Firenze), Nicola Cassata (Palermo), Giacomo Colussi (Milano), Silvia Consolo (Milano), Ciro Corrado (Palermo), Simone Cortazzi (Asti), Raffaella Cravero (Biella), Olga Credendino (Napoli), Marco D'Amico (Como), Vincenzo De Biase (Verona), Delia Davoli (Modena), Lucia Del Vecchio (Lecco), Chiara De Philippis (Milano), Roberta Fenoglio (Torino), Lucrezia Furian (Padova), Andrea Galassi (Milano), Giovanni Gambaro (Verona), Paolo Giannattasio (Napoli), Fabio Giglio (Milano), Mario Giordano (Bari), Gina Gregorini (Brescia), Cristina Grimoldi (Firenze), Francesco Iannuzzella (Reggio Emilia), Alessandro Inzoli (Cremona), Andrea Mancini ?+(Bari), Maria Cristina Mancuso (Milano), Silvio Maringhini (Palermo), Jacopo Mariotti (Milano), Marco Martini (Arezzo), Alessandra Messuerotti (Torino), Sabrina Milan Manani (Vicenza), Concetta Micalizzi (Genova), Cristina Milocco (Monfalcone), Alessandro Naticchia (Roma), Maria Neunhauserer (Brunico), Francesco Onida (Milano), Fabio Paglialonga (Milano), Giuseppe Palladino (Salerno), Antonello Pani (Cagliari), Werner Passler (Bolzano), Jacopo Peccatori (Milano), Valentina Pellu (Aosta), Federico Pieruzzi (Monza), Lucia Pisano (Desio), Gian Marco Podda (Milano), Vera Polaschi (Milano), Ilaria Possenti (Alessandria), Leonardo Potenza (Modena), Federica Ravera (Milano), Roberto Rona (Monza), Attilio Rovelli (Monza), Patrizia Rovere Querini (Milano), Domenico Russo (Napoli), Rodolfo Russo (Genova), Chiara Salviani (Brescia), Paola Lucia Serbelloni (Vimercate), Giuseppe Seminara (Catania), Giacomo Simonetti (Bellinzona), Danio Somenzi (Reggio Emilia), Tiziana Stellato (Monza), Sara Testa (Milano), Aristide Torre (Nocera I.), Chiara Trenti (Reggio Emilia), Silvia Trisolini (Roma), Simona Verdesca (Milano), Marta Verna (Monza), Giuseppe Visconti (Palermo), and Marco Zecca (Pavia). GA, SL, LP, GP, BS,VC, DC, GL, FT, SS, MS, LM, EMR, NBG, GM, MS, MC, FC, DC, and ST contributed to the design of the study, to the analysis of the results, and to the writing of the manuscript. All authors read and approved the final version of the manuscript.
Publisher Copyright:
© 2021 International Society of Nephrology
PY - 2021
Y1 - 2021
N2 - 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 7595 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 1000 person-years. The disease rate was 7.47 per 1000 person-years 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.
AB - 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 7595 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 1000 person-years. The disease rate was 7.47 per 1000 person-years 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.
KW - aHUS
KW - complement genes
KW - penetrance
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U2 - 10.1016/j.ekir.2021.03.885
DO - 10.1016/j.ekir.2021.03.885
M3 - Article
AN - SCOPUS:85104649496
VL - 6
SP - 1614
EP - 1621
JO - Kidney International Reports
JF - Kidney International Reports
SN - 2468-0249
IS - 6
ER -