Clinical and molecular phenotype of Aicardi-Goutieres syndrome.
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.
Rice
Gillian
G
Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, LS9 7TF, UK.
Patrick
Teresa
T
Parmar
Rekha
R
Taylor
Claire F
CF
Aeby
Alec
A
Aicardi
Jean
J
Artuch
Rafael
R
Montalto
Simon Attard
SA
Bacino
Carlos A
CA
Barroso
Bruno
B
Baxter
Peter
P
Benko
Willam S
WS
Bergmann
Carsten
C
Bertini
Enrico
E
Biancheri
Roberta
R
Blair
Edward M
EM
Blau
Nenad
N
Bonthron
David T
DT
Briggs
Tracy
T
Brueton
Louise A
LA
Brunner
Han G
HG
Burke
Christopher J
CJ
Carr
Ian M
IM
Carvalho
Daniel R
DR
Chandler
Kate E
KE
Christen
Hans-Jurgen
HJ
Corry
Peter C
PC
Cowan
Frances M
FM
Cox
Helen
H
D'Arrigo
Stefano
S
Dean
John
J
De Laet
Corinne
C
De Praeter
Claudine
C
Dery
Catherine
C
Ferrie
Colin D
CD
Flintoff
Kim
K
Frints
Suzanna G M
SG
Garcia-Cazorla
Angels
A
Gener
Blanca
B
Goizet
Cyril
C
Goutieres
Francoise
F
Green
Andrew J
AJ
Guet
Agnes
A
Hamel
Ben C J
BC
Hayward
Bruce E
BE
Heiberg
Arvid
A
Hennekam
Raoul C
RC
Husson
Marie
M
Jackson
Andrew P
AP
Jayatunga
Rasieka
R
Jiang
Yong-Hui
YH
Kant
Sarina G
SG
Kao
Amy
A
King
Mary D
MD
Kingston
Helen M
HM
Klepper
Joerg
J
van der Knaap
Marjo S
MS
Kornberg
Andrew J
AJ
Kotzot
Dieter
D
Kratzer
Wilfried
W
Lacombe
Didier
D
Lagae
Lieven
L
Landrieu
Pierre Georges
PG
Lanzi
Giovanni
G
Leitch
Andrea
A
Lim
Ming J
MJ
Livingston
John H
JH
Lourenco
Charles M
CM
Lyall
E G Hermione
EG
Lynch
Sally A
SA
Lyons
Michael J
MJ
Marom
Daphna
D
McClure
John P
JP
McWilliam
Robert
R
Melancon
Serge B
SB
Mewasingh
Leena D
LD
Moutard
Marie-Laure
ML
Nischal
Ken K
KK
Ostergaard
John R
JR
Prendiville
Julie
J
Rasmussen
Magnhild
M
Rogers
R Curtis
RC
Roland
Dominique
D
Rosser
Elisabeth M
EM
Rostasy
Kevin
K
Roubertie
Agathe
A
Sanchis
Amparo
A
Schiffmann
Raphael
R
Scholl-Burgi
Sabine
S
Seal
Sunita
S
Shalev
Stavit A
SA
Corcoles
C Sierra
CS
Sinha
Gyan P
GP
Soler
Doriette
D
Spiegel
Ronen
R
Stephenson
John B P
JB
Tacke
Uta
U
Tan
Tiong Yang
TY
Till
Marianne
M
Tolmie
John L
JL
Tomlin
Pam
P
Vagnarelli
Federica
F
Valente
Enza Maria
EM
Van Coster
Rudy N A
RN
Van der Aa
Nathalie
N
Vanderver
Adeline
A
Vles
Johannes S H
JS
Voit
Thomas
T
Wassmer
Evangeline
E
Weschke
Bernhard
B
Whiteford
Margo L
ML
Willemsen
Michel A A
MA
Zankl
Andreas
A
Zuberi
Sameer M
SM
Orcesi
Simona
S
Fazzi
Elisa
E
Lebon
Pierre
P
Crow
Yanick J
YJ
D000293:Adolescent; D000328:Adult; D001480:Basal Ganglia Diseases / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology; D002114:Calcinosis / Q000235:genetics / Q000473:pathology; D002647:Chilblains / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005090:Exodeoxyribonucleases / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008218:Lymphocytosis / Q000134:cerebrospinal fluid / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics; D016914:Ribonuclease H / Q000235:genetics; D013577:Syndrome
D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; C091139:ribonuclease HII; D016914:Ribonuclease H