Aicardi-Goutières Syndrome 5 via the SAMHD1 Gene

Aicardi-Goutiéres syndrome (AGS) is a rare, early-onset, progressive encephalopathy typically characterized by basal ganglia calcification, white matter abnormalities, and cerebral atrophy (Crow and Livingston 2008; Crow and Manel 2015). Affected individuals can present with progressive microcephaly, hypotonia, dystonia, seizures, spastic quadriplegia, and severe developmental delay (Crow 2014). Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, and systemic lupus erythematosus are also associated with the AGS spectrum of disease (Crow et al. 2015). Cerebrospinal fluid analyses show lymphocytosis and increased type I interferon activity. AGS individuals are often misdiagnosed with congenital infections due to similar presentation. Onset can occur in utero (~25%), while the majority of patients present within the first year of life (~70%) (Crow et al. 2015). Recently, six interferon-stimulated genes were measured and found to be useful biomarkers in most AGS patients (Rice et al. 2013).

Aicardi-Goutières Syndrome 5 is inherited in an autosomal recessive manner due to pathogenic variants in SAMHD1, located on chromosome 20pter-q12. SAMHD1 encodes the sterile alpha motif domain and HD domain containing protein 1 (SAMHD1) which is a nucleic-acid-binding protein. Most pathogenic variants have been found to result in altered protein subcellular localization that results in cytosolic accumulation of the SAMHD1 protein (Goncalves et al. 2012). Missense, nonsense, splicing, and small deletions/duplications, and about 10 gross deletions have all been reported in the SAMHD1 gene (Human Gene Mutation Database).

In a recent comprehensive study of 374 patients (299 families) with a molecular diagnosis of AGS, pathogenic variants were found in the following percentages: 23% TREX1, 5% RNASEH2A, 36% RNASEH2B, 12% RNASEH2C, 13% SAMHD1, 7% ADAR, and 3% IFIH1 (Crow et al. 2015).

Thus far, about 10 large deletions involving the SAMHD1 gene have been reported.

This test provides full coverage of all coding exons of the SAMHD1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.