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.