Clinical and molecular phenotype of Aicardi-Goutières syndrome

Gillian Rice, Teresa Patrick, Rekha Parmar, Claire F. Taylor, Alec Aeby, Jean Aicardi, Rafael Artuch, Simon Attard Montalto, Carlos A. Bacino, Bruno Barroso, Peter Baxter, William Benko, Carsten Bergmann, Enrico Bertini, Roberta Biancheri, Edward M. Blair, Nenad Blau, David T. Bonthron, Tracy Briggs, Louise A. BruetonHan G. Brunner, Christopher J. Burke, Ian M. Carr, Daniel R. Carvalho, Kate E. Chandler, Hans Jürgen Christen, Peter C. Corry, Frances M. Cowan, Helen Cox, Stefano D'Arrigo, John Dean, Corinne De Laet, Claudine De Praeter, Catherine Déry, Colin D. Ferrie, Kim Flintoff, Suzanna G.M. Frints, Angels Garcia-Cazorla, Blanca Gener, Cyril Goizet, Françoise Goutières, Andrew J. Green, Agnès Guët, Ben C.J. Hamel, Bruce E. Hayward, Arvid Heiberg, Raoul C. Hennekam, Marie Husson, Andrew P. Jackson, Rasieka Jayatunga, Yong Hui Jiang, Sarina G. Kant, Amy Kao, Mary D. King, Helen M. Kingston, Joerg Klepper, Marjo S. Van Der Knaap, Andrew J. Kornberg, Dieter Kotzot, Wilfried Kratzer, Didier Lacombe, Lieven Lagae, Pierre Georges Landrieu, Giovanni Lanzi, Andrea Leitch, Ming J. Lim, John H. Livingston, Charles M. Lourenco, E. G.Hermione Lyall, Sally A. Lynch, Michael J. Lyons, Daphna Marom, John P. McClure, Robert McWilliam, Serge B. Melancon, Leena D. Mewasingh, Marie Laure Moutard, Ken K. Nischal, John R. Østergaard, Julie Prendiville, Magnhild Rasmussen, R. Curtis Rogers, Dominique Roland, Elisabeth M. Rosser, Kevin Rostasy, Agathe Roubertie, Amparo Sanchis, Raphael Schiffmann, Sabine Scholl-Bürgi, Sunita Seal, Stavit A. Shalev, C. Sierra Corcoles, Gyan P. Sinha, Doriette Soler, Ronen Spiegel, John B.P. Stephenson, Uta Tacke, Yang Tan Tiong, Marianne Till, John L. Tolmie, Pam Tomlin, Federica Vagnarelli, Enza Maria Valente, Rudy N.A. Van Coster, Nathalie Van Der Aa, Adeline Vanderver, Johannes S.H. Vles, Thomas Voit, Evangeline Wassmer, Bernhard Weschke, Margo L. Whiteford, Michel A.A. Willemsen, Andreas Zankl, Sameer M. Zuberi, Simona Orcesi, Elisa Fazzi, Pierre Lebon, Yanick J. Crow

Research output: Contribution to journalArticle

240 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)713-725
Number of pages13
JournalAmerican Journal of Human Genetics
Volume81
Issue number4
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W., Bergmann, C., Bertini, E., Biancheri, R., Blair, E. M., Blau, N., Bonthron, D. T., Briggs, T., ... Crow, Y. J. (2007). Clinical and molecular phenotype of Aicardi-Goutières syndrome. American Journal of Human Genetics, 81(4), 713-725. https://doi.org/10.1086/521373