SAMHD1 – Aicardi-Goutières Syndrome

Aicardi-Goutières syndrome (AGS) is a monogenic interferonopathy characterized by early-onset encephalopathy, acquired microcephaly, intracranial calcification, chronic cutaneous inflammation, and elevated type I interferon. SAMHD1 (HGNC:15925) encodes a deoxynucleoside triphosphate triphosphohydrolase. Biallelic loss-of-function and missense variants in SAMHD1 cause AGS type 5 (MONDO:0018866) in an autosomal recessive manner.

Genetic evidence includes compound heterozygous null and missense variants segregating in multiple families, with at least 24 probands reported worldwide ([PMID:20358604]; [PMID:25246298]; [PMID:29239743]). Segregation in sibships confirms recessive inheritance. The variant spectrum comprises missense, nonsense, frameshift, and splice-site alleles. For example, c.1634T>G (p.Phe545Cys) in trans with c.490C>T (p.Arg164Ter) segregates with disease in a sibship ([PMID:20358604]).

Clinically, patients present in the neonatal period or early infancy with developmental delay (HP:0001250), acquired microcephaly (HP:0000252), spasticity (HP:0001257), seizures, chilblain lesions, chronic arthropathy, and joint contractures. Phenotypic variability ranges from severe encephalopathy to predominant cutaneous and articular features.

Functional studies demonstrate that SAMHD1 deficiency markedly diminishes unscheduled DNA synthesis in patient fibroblasts, differentiating AGS from Cockayne syndrome ([PMID:36405817]). AGS-associated SAMHD1 truncation and missense variants mislocalize to the cytosol and impair nucleic-acid binding ([PMID:22461318]). SAMHD1 loss leads to elevated intracellular dNTP pools, DNA damage signaling, and constitutive activation of the cGAS–STING–IRF3 pathway, driving type I interferon expression ([PMID:24445253]; [PMID:29311560]).

Overall, the consistent genetic and functional concordance supports a definitive gene–disease relationship. SAMHD1 testing is recommended in early-onset neuroinflammatory and autoinflammatory presentations. Key take‐home: Early identification of SAMHD1 variants enables accurate diagnosis of AGS and guides timely immunomodulatory interventions.

References

• American journal of medical genetics. Part A • 2010 • Familial Aicardi-Goutières syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures [PMID:20358604]
• Journal of child neurology • 2015 • A possible genotype-phenotype correlation in Ashkenazi-Jewish individuals with Aicardi-Goutières syndrome associated with SAMHD1 mutation [PMID:25246298]
• Pediatric neurology • 2018 • Phenotypic and Molecular Spectrum of Aicardi-Goutières Syndrome: A Study of 24 Patients [PMID:29239743]
• Frontiers in pediatrics • 2022 • Aicardi-Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test. [PMID:36405817]
• Human mutation • 2012 • SAMHD1 is a nucleic-acid binding protein that is mislocalized due to aicardi-goutières syndrome-associated mutations [PMID:22461318]
• Annals of the rheumatic diseases • 2015 • SAMHD1 prevents autoimmunity by maintaining genome stability. [PMID:24445253]

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