Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

Crow, Yanick J.; Chase, Diana S.; Lowenstein Schmidt, Johanna; Szynkiewicz, Marcin; Forte, Gabriella M.A.; Gornall, Hannah L.; Oojageer, Anthony; Anderson, Beverley; Pizzino, Amy; Helman, Guy; Abdel-Hamid, Mohamed S.; Abdel-Salam, Ghada M.; Ackroyd, Sam; Aeby, Alec; Agosta, Guillermo; Albin, Catherine; Allon-Shalev, Stavit; Arellano, Montse; Ariaudo, Giada; Aswani, Vijay; Babul-Hirji, Riyana; Baildam, Eileen M.; Bahi-Buisson, Nadia; Bailey, Kathryn M.; Barnerias, Christine; Barth, Magalie; Battini, Roberta; Beresford, Michael W.; Bernard, Genevi?ve; Bianchi, Marika; Billette de Villemeur, Thierry; Blair, Edward M.; Bloom, Miriam; Burlina, Alberto B.; Luisa Carpanelli, Maria; Carvalho, Daniel R.; Castro-Gago, Manuel; Cavallini, Anna; Cereda, Cristina; Chandler, Kate E.; Chitayat, David A.; Collins, Abigail E.; Sierra Corcoles, Concepcion; Cordeiro, Nuno J.V.; Crichiutti, Giovanni; Dabydeen, Lyvia; Dale, Russell C.; D?Arrigo, Stefano; De Goede, Christian G.E.L.; De Laet, Corinne; De Wael...

Abstract

Aicardi–Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease‐onset (74 patients; 22.8% of all patients where data were available), or a post‐natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub‐acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non‐syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow‐up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi‐Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon‐stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon‐stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi–Goutières syndrome‐related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. © 2015 Wiley Periodicals, Inc.

Citation

Crow, Y. J., Chase, D. S., Lowenstein Schmidt, J., Szynkiewicz, M., Forte, G. M., Gornall, H. L., …Rice, G. I. (2015). Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American Journal of Medical Genetics Part A, 167(2), 296-312. https://doi.org/10.1002/ajmg.a.36887

• Journal Article Type: Article
• Acceptance Date: Oct 31, 2014
• Online Publication Date: Jan 16, 2015
• Publication Date: 2015-02
• Deposit Date: Feb 15, 2017
• Journal: American Journal of Medical Genetics Part A
• Print ISSN: 1552-4825
• Electronic ISSN: 1552-4833
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 167
• Issue: 2
• Pages: 296-312
• DOI: https://doi.org/10.1002/ajmg.a.36887
• Public URL: https://nottingham-repository.worktribe.com/output/1110931
• Publisher URL: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.36887
• Additional Information: Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1; ; Yanick J. Crow Diana S. Chase Johanna Lowenstein Schmidt Marcin Szynkiewicz Gabriella M.A. Forte Hannah L. Gornall Anthony Oojageer Beverley Anderson Amy Pizzino Guy Helman Mohamed S. Abdel‐Hamid Ghada M. Abdel‐Salam Sam Ackroyd Alec Aeby Guillermo Agosta Catherine Albin Stavit Allon‐Shalev Montse Arellano Giada Ariaudo Vijay Aswani Riyana Babul‐Hirji Eileen M. Baildam Nadia Bahi‐Buisson Kathryn M. Bailey Christine Barnerias Magalie Barth Roberta Battini Michael W. Beresford Geneviève Bernard Marika Bianchi Thierry Billette de Villemeur Edward M. Blair Miriam Bloom Alberto B. Burlina Maria Luisa Carpanelli Daniel R. Carvalho Manuel Castro‐Gago Anna Cavallini Cristina Cereda Kate E. Chandler David A. Chitayat Abigail E. Collins Concepcion Sierra Corcoles Nuno J.V. Cordeiro Giovanni Crichiutti Lyvia Dabydeen Russell C. Dale Stefano D′Arrigo Christian G.E.L. De Goede Corinne De Laet Liesbeth M.H. De Waele Ines Denzler Isabelle Desguerre Koenraad Devriendt Maja Di Rocco Michael C. Fahey Elisa Fazzi Colin D. Ferrie António Figueiredo Blanca Gener Cyril Goizet Nirmala R. Gowrinathan Kalpana Gowrishankar Donncha Hanrahan Bertrand Isidor Bülent Kara Nasaim Khan Mary D. King Edwin P. Kirk Ram Kumar Lieven Lagae Pierre Landrieu Heinz Lauffer Vincent Laugel Roberta La Piana Ming J. Lim Jean‐Pierre S.‐M. Lin Tarja Linnankivi Mark T. Mackay Daphna R. Marom Charles Marques Lourenço Shane A. McKee Isabella Moroni Jenny E.V. Morton Marie‐Laure Moutard Kevin Murray Rima Nabbout Sheela Nampoothiri Noemi Nunez‐Enamorado Patrick J. Oades Ivana Olivieri John R. Ostergaard Belén Pérez‐Dueñas Julie S. Prendiville Venkateswaran Ramesh Magnhild Rasmussen Luc Régal Federica Ricci Marlène Rio Diana Rodriguez Agathe Roubertie Elisabetta Salvatici Karin A. Segers Gyanranjan P. Sinha Doriette Soler Ronen Spiegel Tommy I. Stödberg Rachel Straussberg Kathryn J. Swoboda Mohnish Suri Uta Tacke Tiong Y. Tan Johann te Water Naude Keng Wee Teik Maya Mary Thomas Marianne Till Davide Tonduti Enza Maria Valente Rudy Noel Van Coster Marjo S. van der Knaap Grace Vassallo Raymon Vijzelaar Julie Vogt Geoffrey B. Wallace Evangeline Wassmer Hannah J. Webb William P. Whitehouse Robyn N. Whitney Maha S. Zaki Sameer M. Zuberi John H. Livingston Flore Rozenberg Pierre Lebon Adeline Vanderver Simona Orcesi Gillian I. Rice