Clinical and molecular phenotype of Aicardi-Goutieres syndrome.Citation formats

  • External authors:
  • 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
  • Louise A Brueton
  • Han G Brunner
  • Christopher J Burke
  • Ian M Carr
  • Daniel R Carvalho
  • Kate E Chandler
  • Hans-Jurgen Christen
  • Peter C Corry
  • Frances M Cowan
  • Helen Cox
  • Stefano D'Arrigo
  • John Dean
  • Corinne De Laet
  • Claudine De Praeter
  • Catherine Dery
  • Colin D Ferrie
  • Kim Flintoff
  • Suzanna G M Frints
  • Angels Garcia-Cazorla
  • Blanca Gener
  • Cyril Goizet
  • Francoise Goutieres
  • Andrew J Green
  • Agnes Guet
  • 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 Ostergaard
  • Julie Prendiville
  • Magnhild Rasmussen
  • R Curtis Rogers
  • Dominique Roland
  • Elisabeth M Rosser
  • Kevin Rostasy
  • Agathe Roubertie
  • Amparo Sanchis
  • Raphael Schiffmann
  • Sabine Scholl-Burgi
  • 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
  • John R. Østergaard
  • Yang Tan Tiong

Standard

Clinical and molecular phenotype of Aicardi-Goutieres syndrome. / 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-Jurgen; Corry, Peter C; Cowan, Frances M; Cox, Helen; D'Arrigo, Stefano; Dean, John; De Laet, Corinne; De Praeter, Claudine; Dery, Catherine; Ferrie, Colin D; Flintoff, Kim; Frints, Suzanna G M; Garcia-Cazorla, Angels; Gener, Blanca; Goizet, Cyril; Goutieres, Francoise; Green, Andrew J; Guet, Agnes; 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; van der Knaap, Marjo S; Kornberg, Andrew J; Kotzot, Dieter; 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; Ostergaard, John R; Prendiville, Julie; Rasmussen, Magnhild; Rogers, R Curtis; Roland, Dominique; Rosser, Elisabeth M; Rostasy, Kevin; Roubertie, Agathe; Sanchis, Amparo; Schiffmann, Raphael; Scholl-Burgi, Sabine; 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; Van Coster, Rudy N A; Van der Aa, Nathalie; Vanderver, Adeline; Vles, Johannes S H; Voit, Thomas; Wassmer, Evangeline; Weschke, Bernhard; Whiteford, Margo L; Willemsen, Michel A A; Zankl, Andreas; Zuberi, Sameer M; Orcesi, Simona; Fazzi, Elisa; Lebon, Pierre; Crow, Yanick J; Østergaard, John R.; Tiong, Yang Tan.

In: American Journal of Human Genetics, Vol. 81, No. 4, 10.2007, p. 713-725.

Research output: Contribution to journalArticle

Harvard

Rice, G, 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, H-J, Corry, PC, Cowan, FM, Cox, H, D'Arrigo, S, Dean, J, De Laet, C, De Praeter, C, Dery, C, Ferrie, CD, Flintoff, K, Frints, SGM, Garcia-Cazorla, A, Gener, B, Goizet, C, Goutieres, F, Green, AJ, Guet, A, Hamel, BCJ, Hayward, BE, Heiberg, A, Hennekam, RC, Husson, M, Jackson, AP, Jayatunga, R, Jiang, Y-H, 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, EGH, Lynch, SA, Lyons, MJ, Marom, D, McClure, JP, McWilliam, R, Melancon, SB, Mewasingh, LD, Moutard, M-L, 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, JBP, Tacke, U, Tan, TY, Till, M, Tolmie, JL, Tomlin, P, Vagnarelli, F, Valente, EM, Van Coster, RNA, Van der Aa, N, Vanderver, A, Vles, JSH, Voit, T, Wassmer, E, Weschke, B, Whiteford, ML, Willemsen, MAA, Zankl, A, Zuberi, SM, Orcesi, S, Fazzi, E, Lebon, P, Crow, YJ, Østergaard, JR & Tiong, YT 2007, 'Clinical and molecular phenotype of Aicardi-Goutieres syndrome.', American Journal of Human Genetics, vol. 81, no. 4, pp. 713-725. https://doi.org/10.1086/521373

APA

Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., ... Tiong, Y. T. (2007). Clinical and molecular phenotype of Aicardi-Goutieres syndrome. American Journal of Human Genetics, 81(4), 713-725. https://doi.org/10.1086/521373

Vancouver

Rice G, Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. American Journal of Human Genetics. 2007 Oct;81(4):713-725. https://doi.org/10.1086/521373

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-Jurgen ; Corry, Peter C ; Cowan, Frances M ; Cox, Helen ; D'Arrigo, Stefano ; Dean, John ; De Laet, Corinne ; De Praeter, Claudine ; Dery, Catherine ; Ferrie, Colin D ; Flintoff, Kim ; Frints, Suzanna G M ; Garcia-Cazorla, Angels ; Gener, Blanca ; Goizet, Cyril ; Goutieres, Francoise ; Green, Andrew J ; Guet, Agnes ; 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 ; van der Knaap, Marjo S ; Kornberg, Andrew J ; Kotzot, Dieter ; 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 ; Ostergaard, John R ; Prendiville, Julie ; Rasmussen, Magnhild ; Rogers, R Curtis ; Roland, Dominique ; Rosser, Elisabeth M ; Rostasy, Kevin ; Roubertie, Agathe ; Sanchis, Amparo ; Schiffmann, Raphael ; Scholl-Burgi, Sabine ; 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 ; Van Coster, Rudy N A ; Van der Aa, Nathalie ; Vanderver, Adeline ; Vles, Johannes S H ; Voit, Thomas ; Wassmer, Evangeline ; Weschke, Bernhard ; Whiteford, Margo L ; Willemsen, Michel A A ; Zankl, Andreas ; Zuberi, Sameer M ; Orcesi, Simona ; Fazzi, Elisa ; Lebon, Pierre ; Crow, Yanick J ; Østergaard, John R. ; Tiong, Yang Tan. / Clinical and molecular phenotype of Aicardi-Goutieres syndrome. In: American Journal of Human Genetics. 2007 ; Vol. 81, No. 4. pp. 713-725.

Bibtex

@article{3c4306cc901f4faea8569b029b9f87d7,
title = "Clinical and molecular phenotype of Aicardi-Goutieres syndrome.",
abstract = "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.",
keywords = "Adolescent, Adult, cerebrospinal fluid: Basal Ganglia Diseases, pathology: Brain, genetics: Calcinosis, genetics: Chilblains, Child, Child, Preschool, DNA Mutational Analysis, genetics: Exodeoxyribonucleases, Female, Humans, Infant, Infant, Newborn, cerebrospinal fluid: Lymphocytosis, Male, Molecular Sequence Data, Mutation, Phenotype, genetics: Phosphoproteins, genetics: Ribonuclease H, Syndrome",
author = "Gillian Rice and Teresa Patrick and Rekha Parmar and Taylor, {Claire F} and Alec Aeby and Jean Aicardi and Rafael Artuch and Montalto, {Simon Attard} and Bacino, {Carlos A} and Bruno Barroso and Peter Baxter and Benko, {Willam S} and Carsten Bergmann and Enrico Bertini and Roberta Biancheri and Blair, {Edward M} and Nenad Blau and Bonthron, {David T} and Tracy Briggs and Brueton, {Louise A} and Brunner, {Han G} and Burke, {Christopher J} and Carr, {Ian M} and Carvalho, {Daniel R} and Chandler, {Kate E} and Hans-Jurgen Christen and Corry, {Peter C} and Cowan, {Frances M} and Helen Cox and Stefano D'Arrigo and John Dean and {De Laet}, Corinne and {De Praeter}, Claudine and Catherine Dery and Ferrie, {Colin D} and Kim Flintoff and Frints, {Suzanna G M} and Angels Garcia-Cazorla and Blanca Gener and Cyril Goizet and Francoise Goutieres and Green, {Andrew J} and Agnes Guet and Hamel, {Ben C J} and Hayward, {Bruce E} and Arvid Heiberg and Hennekam, {Raoul C} and Marie Husson and Jackson, {Andrew P} and Rasieka Jayatunga and Yong-Hui Jiang and Kant, {Sarina G} and Amy Kao and King, {Mary D} and Kingston, {Helen M} and Joerg Klepper and {van der Knaap}, {Marjo S} and Kornberg, {Andrew J} and Dieter Kotzot and Wilfried Kratzer and Didier Lacombe and Lieven Lagae and Landrieu, {Pierre Georges} and Giovanni Lanzi and Andrea Leitch and Lim, {Ming J} and Livingston, {John H} and Lourenco, {Charles M} and Lyall, {E G Hermione} and Lynch, {Sally A} and Lyons, {Michael J} and Daphna Marom and McClure, {John P} and Robert McWilliam and Melancon, {Serge B} and Mewasingh, {Leena D} and Marie-Laure Moutard and Nischal, {Ken K} and Ostergaard, {John R} and Julie Prendiville and Magnhild Rasmussen and Rogers, {R Curtis} and Dominique Roland and Rosser, {Elisabeth M} and Kevin Rostasy and Agathe Roubertie and Amparo Sanchis and Raphael Schiffmann and Sabine Scholl-Burgi and Sunita Seal and Shalev, {Stavit A} and Corcoles, {C Sierra} and Sinha, {Gyan P} and Doriette Soler and Ronen Spiegel and Stephenson, {John B P} and Uta Tacke and Tan, {Tiong Yang} and Marianne Till and Tolmie, {John L} and Pam Tomlin and Federica Vagnarelli and Valente, {Enza Maria} and {Van Coster}, {Rudy N A} and {Van der Aa}, Nathalie and Adeline Vanderver and Vles, {Johannes S H} and Thomas Voit and Evangeline Wassmer and Bernhard Weschke and Whiteford, {Margo L} and Willemsen, {Michel A A} and Andreas Zankl and Zuberi, {Sameer M} and Simona Orcesi and Elisa Fazzi and Pierre Lebon and Crow, {Yanick J} and {\O}stergaard, {John R.} and Tiong, {Yang Tan}",
note = "K08 NS060695, NINDS NIH HHS, United StatesMC_U127580972, Medical Research Council, United Kingdom",
year = "2007",
month = "10",
doi = "10.1086/521373",
language = "English",
volume = "81",
pages = "713--725",
journal = "Am J Hum Genet",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

AU - Rice, Gillian

AU - Patrick, Teresa

AU - Parmar, Rekha

AU - Taylor, Claire F

AU - Aeby, Alec

AU - Aicardi, Jean

AU - Artuch, Rafael

AU - Montalto, Simon Attard

AU - Bacino, Carlos A

AU - Barroso, Bruno

AU - Baxter, Peter

AU - Benko, Willam S

AU - Bergmann, Carsten

AU - Bertini, Enrico

AU - Biancheri, Roberta

AU - Blair, Edward M

AU - Blau, Nenad

AU - Bonthron, David T

AU - Briggs, Tracy

AU - Brueton, Louise A

AU - Brunner, Han G

AU - Burke, Christopher J

AU - Carr, Ian M

AU - Carvalho, Daniel R

AU - Chandler, Kate E

AU - Christen, Hans-Jurgen

AU - Corry, Peter C

AU - Cowan, Frances M

AU - Cox, Helen

AU - D'Arrigo, Stefano

AU - Dean, John

AU - De Laet, Corinne

AU - De Praeter, Claudine

AU - Dery, Catherine

AU - Ferrie, Colin D

AU - Flintoff, Kim

AU - Frints, Suzanna G M

AU - Garcia-Cazorla, Angels

AU - Gener, Blanca

AU - Goizet, Cyril

AU - Goutieres, Francoise

AU - Green, Andrew J

AU - Guet, Agnes

AU - Hamel, Ben C J

AU - Hayward, Bruce E

AU - Heiberg, Arvid

AU - Hennekam, Raoul C

AU - Husson, Marie

AU - Jackson, Andrew P

AU - Jayatunga, Rasieka

AU - Jiang, Yong-Hui

AU - Kant, Sarina G

AU - Kao, Amy

AU - King, Mary D

AU - Kingston, Helen M

AU - Klepper, Joerg

AU - van der Knaap, Marjo S

AU - Kornberg, Andrew J

AU - Kotzot, Dieter

AU - Kratzer, Wilfried

AU - Lacombe, Didier

AU - Lagae, Lieven

AU - Landrieu, Pierre Georges

AU - Lanzi, Giovanni

AU - Leitch, Andrea

AU - Lim, Ming J

AU - Livingston, John H

AU - Lourenco, Charles M

AU - Lyall, E G Hermione

AU - Lynch, Sally A

AU - Lyons, Michael J

AU - Marom, Daphna

AU - McClure, John P

AU - McWilliam, Robert

AU - Melancon, Serge B

AU - Mewasingh, Leena D

AU - Moutard, Marie-Laure

AU - Nischal, Ken K

AU - Ostergaard, John R

AU - Prendiville, Julie

AU - Rasmussen, Magnhild

AU - Rogers, R Curtis

AU - Roland, Dominique

AU - Rosser, Elisabeth M

AU - Rostasy, Kevin

AU - Roubertie, Agathe

AU - Sanchis, Amparo

AU - Schiffmann, Raphael

AU - Scholl-Burgi, Sabine

AU - Seal, Sunita

AU - Shalev, Stavit A

AU - Corcoles, C Sierra

AU - Sinha, Gyan P

AU - Soler, Doriette

AU - Spiegel, Ronen

AU - Stephenson, John B P

AU - Tacke, Uta

AU - Tan, Tiong Yang

AU - Till, Marianne

AU - Tolmie, John L

AU - Tomlin, Pam

AU - Vagnarelli, Federica

AU - Valente, Enza Maria

AU - Van Coster, Rudy N A

AU - Van der Aa, Nathalie

AU - Vanderver, Adeline

AU - Vles, Johannes S H

AU - Voit, Thomas

AU - Wassmer, Evangeline

AU - Weschke, Bernhard

AU - Whiteford, Margo L

AU - Willemsen, Michel A A

AU - Zankl, Andreas

AU - Zuberi, Sameer M

AU - Orcesi, Simona

AU - Fazzi, Elisa

AU - Lebon, Pierre

AU - Crow, Yanick J

AU - Østergaard, John R.

AU - Tiong, Yang Tan

N1 - K08 NS060695, NINDS NIH HHS, United StatesMC_U127580972, Medical Research Council, United Kingdom

PY - 2007/10

Y1 - 2007/10

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - cerebrospinal fluid: Basal Ganglia Diseases

KW - pathology: Brain

KW - genetics: Calcinosis

KW - genetics: Chilblains

KW - Child

KW - Child, Preschool

KW - DNA Mutational Analysis

KW - genetics: Exodeoxyribonucleases

KW - Female

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - cerebrospinal fluid: Lymphocytosis

KW - Male

KW - Molecular Sequence Data

KW - Mutation

KW - Phenotype

KW - genetics: Phosphoproteins

KW - genetics: Ribonuclease H

KW - Syndrome

U2 - 10.1086/521373

DO - 10.1086/521373

M3 - Article

C2 - 17846997

VL - 81

SP - 713

EP - 725

JO - Am J Hum Genet

JF - Am J Hum Genet

SN - 0002-9297

IS - 4

ER -