Clinical and molecular phenotype of Aicardi-Goutieres 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, Willam S. Benko, Carsten Bergmann, Enrico Bertini, Roberta Biancheri, Edward M. Blair, Nenad Blau, David T. Bonthron, Tracy Briggs, Louise A. Brueton, Han 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, Tiong Yang Tan, 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
The American Journal of Human Genetics. 2007-10-01; 81(4): 713-725
DOI: 10.1086/521373


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1. Am J Hum Genet. 2007 Oct;81(4):713-25. Epub 2007 Sep 4.

Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Rice G(1), Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J, Artuch R, Montalto
SA, Bacino CA, Barroso B, Baxter P, Benko WS, Bergmann C, Bertini E, Biancheri R,
Blair EM, Blau N, Bonthron DT, Briggs T, Brueton LA, Brunner HG, Burke CJ, Carr
IM, Carvalho DR, Chandler KE, Christen HJ, Corry PC, Cowan FM, Cox H, D’Arrigo S,
Dean J, De Laet C, De Praeter C, Dery C, Ferrie CD, Flintoff K, Frints SG,
Garcia-Cazorla A, Gener B, Goizet C, Goutieres F, Green AJ, Guet A, Hamel BC,
Hayward BE, Heiberg A, Hennekam RC, Husson M, Jackson AP, Jayatunga R, Jiang YH,
Kant SG, Kao A, King MD, Kingston HM, Klepper J, van der Knaap MS, Kornberg AJ,
Kotzot D, Kratzer W, Lacombe D, Lagae L, Landrieu PG, Lanzi G, Leitch A, Lim MJ,
Livingston JH, Lourenco CM, Lyall EG, Lynch SA, Lyons MJ, Marom D, McClure JP,
McWilliam R, Melancon SB, Mewasingh LD, Moutard ML, Nischal KK, Ostergaard JR,
Prendiville J, Rasmussen M, Rogers RC, Roland D, Rosser EM, Rostasy K, Roubertie
A, Sanchis A, Schiffmann R, Scholl-Burgi S, Seal S, Shalev SA, Corcoles CS, Sinha
GP, Soler D, Spiegel R, Stephenson JB, Tacke U, Tan TY, Till M, Tolmie JL, Tomlin
P, Vagnarelli F, Valente EM, Van Coster RN, Van der Aa N, Vanderver A, Vles JS,
Voit T, Wassmer E, Weschke B, Whiteford ML, Willemsen MA, Zankl A, Zuberi SM,
Orcesi S, Fazzi E, Lebon P, Crow YJ.

Author information:
(1)Leeds Institute of Molecular Medicine, St James’s University Hospital, Leeds,
LS9 7TF, UK.

Aicardi-Goutieres 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.

DOI: 10.1086/521373
PMCID: PMC2227922
PMID: 17846997 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus