Table 3.

Allelic Disorders

Dyschromatosis symmetrica hereditaria 1 (DSH) 2X
"Pure" spastic paraparesis 3 or childhood-onset paraparesis with normal intellect 4XXX
Autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL) 5X
Systemic lupus erythematosus (SLE) 6XXX
Cree encephalitis 7X
Familial chilblain lupus (FLE) 8XX

Mutation of TREX1 can be associated with additional phenotypes not included in this table [Rice et al 2015].


The heterozygous ADAR p.Gly1007Arg variant, which has been shown to cause autosomal dominant AGS [Rice et al 2012], was previously described in two individuals with DSH demonstrating neurodegeneration with dystonia and intracranial calcification [Tojo et al 2006, Kondo et al 2008].


Richards et al [2007] have shown that C terminus mutation of TREX1 causes RVCL, an autosomal dominant microvascular endotheliopathy variably associated with a retinal vasculopathy, migraine, Raynaud's phenomenon, stroke, and dementia with onset in middle age. This finding raises the possibility, unproven, that the heterozygous parents of children with AGS caused by TREX1 pathogenic variants, at least those with variants in the C terminus of the gene, may be at risk of developing RVCL.


Lee-Kirsch et al [2007b] found heterozygous pathogenic variants in TREX1 in nine of 417 individuals with SLE. This finding raises the possibility that individuals with AGS caused by mutation of TREX1 (as well as their heterozygous parents) may be at risk of developing signs and symptoms similar to SLE.


Linkage analysis and measurement of CSF concentration of IFN-α suggested that AGS and Cree encephalitis were allelic [Crow et al 2003]; this was confirmed when molecular genetic testing revealed that all children with Cree encephalitis are homozygous for the p.Arg164Ter pathogenic variant in TREX1.


Rice et al [2007a] described a heterozygous TREX1 pathogenic variant in affected members of a family with chilblain lupus; a second distinct pathogenic variant was subsequently described by Lee-Kirsch et al [2007a]. Additional pathogenic variants have been described. FLE may also be caused by a heterozygous pathogenic variant in SAMHD1 [Ravenscroft et al 2011].

From: Aicardi-Goutières Syndrome

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