| Author |
Rice, Gillian Patrick, Teresa Parmar, Rekha Taylor, Claire F. Aeby, Alec Aicardi, Jean Artuch, Rafael Montalto, Simon Attard Bacino, Carlos A. Barroso, Bruno Baxter, Peter Benko, Willam S. Bergmann, Carsten Bertini, Enrico Biancheri, Roberta Blair, Edward M. Blau, Nenad Bonthron, David T. Briggs, Tracy Brueton, Louise A. Brunner, Han G. Burke, Christopher J. Carr, Ian M. Carvalho, Daniel R. Chandler, Kate E. Christen, Hans-jürgen Corry, Peter C. Cowan, Frances M. Cox, Helen D’arrigo, Stefano Dean, John Laet, Corinne De De, Praeter Claudine Catherine, Déry Ferrie, Colin D. Flintoff, Kim Frints, Suzanna G. M. Angels, Garcia-cazorla Gener, Blanca Cyril, Goizet Goutières, Françoise Green, Andrew J. Guët, Agnès Hamel, Ben C. J. Hayward, Bruce E. Heiberg, Arvid Hennekam, Raoul C. Husson, Marie Jackson, Andrew P. Jayatunga, Rasieka Jiang, Yong-hui Kant, Sarina G. Kao, Amy King, Mary D. Kingston, Helen M. Klepper, Joerg Knaap, Marjo S. Van Der Kornberg, Andrew J. Dieter, Kotzot Kratzer, Wilfried Lacombe, Didier Lagae, Lieven Landrieu, Pierre Georges Lanzi, Giovanni Leitch, Andrea Lim, Ming J. Livingston, John H. Lourenco, Charles M. Lyall, E. G. Hermione Lynch, Sally A. Lyons, Michael J. Marom, Daphna Mcclure, John P. Mcwilliam, Robert Melancon, Serge B. Mewasingh, Leena D. Moutard, Marie-laure Nischal, Ken K. Østergaard, John R. Prendiville, Julie Rasmussen, Magnhild Rogers, R. Curtis Roland, Dominique Rosser, Elisabeth M. Kevin, Rostasy Agathe, Roubertie Sanchis, Amparo Schiffmann, Raphael Sabine, Scholl-bürgi Seal, Sunita Shalev, Stavit A. Corcoles, C. Sierra Sinha, Gyan P. Soler, Doriette Spiegel, Ronen Stephenson, John B. P. Tacke, Uta Tan, Tiong Yang Till, Marianne Tolmie, John L. Tomlin, Pam Vagnarelli, Federica Valente, Enza Maria Coster, Rudy N. A. Van Van Der Aa, Nathalie Adeline, Vanderver Vles, Johannes S. H. Voit, Thomas Wassmer, Evangeline Weschke, Bernhard Whiteford, Margo L. Willemsen, Michel A. A. Zankl, Andreas Zuberi, Sameer M. Simona, Orcesi Fazzi, Elisa Lebon, Pierre Crow, Yanick J. |
| Abstract |
Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation–positive patients were known to have died ( P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. |
