Table 1.

Molecular Genetic Testing Used in Aicardi-Goutières Syndrome

Gene 1Proportion of AGS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detectable by Method
Sequence analysis 3, 4Gene-targeted deletion/duplication analysis 5
ADAR 7%32/32 alleles 6Unknown 7
IFIH1 3%17/17 alleles 8Unknown 7
RNASEH2A 5%34/34 alleles 9Unknown 7
RNASEH2B 36%~99% 10Unknown 11
RNASEH2C 12%~99% 12, 13Unknown 7
SAMHD1 13%Up to 95% 14Up to 30% 14, 15
TREX1 23%~99% 16Unknown 7

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Sequence analysis of the coding regions and splice sites of ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and TREX1 has identified pathogenic variants in approximately 90%-95% of individuals with clinical and MRI presentation of AGS [Rice et al 2007b, Rice et al 2009, Crow et al 2015].


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


32/32 alleles were detectable by sequence analysis [Crow et al 2015]. A dominant p.Gly1007Arg variant in ADAR has been reported [Rice et al 2012, Livingston et al 2014a]. A recurrent ADAR variant, p.Pro193Ala, is seen in affected persons of European origin.


No deletions or duplications involving ADAR, IFIH1, RNASEH2A, RNASEH2C, or TREX1 have been reported to cause Aicardi-Goutières syndrome.


90% of individuals with biallelic pathogenic variants in RNASEH2B are either homozygous or compound heterozygous for the missense change (p.Ala177Thr).


A deletion of RNASEH2B exons two through five has been reported [Crow et al 2015].


The RNASEH2C variant p.Arg69Trp is seen particularly frequently in Asian (most commonly Pakistani) families and represents an ancient founder variant [Rice et al 2007b].


25/26 alleles [Rice et al 2009] and 47/67 alleles [Crow et al 2015] were detected by sequence analysis. Note: Rice et al [2009] did not perform deletion/duplication analysis and in some families in the study no pathogenic variants were detected.


A recurrent deletion including exon 1 has been observed in several affected individuals of Ashkenazi Jewish ancestry and very likely represents a founder variant [Ramesh et al 2010]. 20/67 alleles in Crow et al [2015] were detectable by deletion/duplication analysis; however, this study included persons of Ashkenazi Jewish descent. Note: A homozygous deletion of ≥1 exons can be suspected by the failure of exons to amplify by PCR. A recurrent splice acceptor site pathogenic variant (c.1411-2A>G) in intron 12 is seen in persons of Amish ancestry and represents an ancient founder variant [Xin et al 2011].


In approximately 100 individuals with TREX1-related AGS, all pathogenic variants were detectable by sequence analysis [Rice et al 2007b, Crow et al 2015]. A recurrent p.Arg164Ter founder variant in TREX1 is seen in individuals of Cree ancestry. The most prevalent TREX1 variant in AGS is a missense change (p.Arg114His) that is particularly common in people from northern Europe.

From: Aicardi-Goutières Syndrome

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