SAMHD1 was first reported in relation to autosomal recessive Aicardi-Goutieres Syndrome Type 5 (OMIM: 612952) in 2009 when it was shown to act as a negative regulator of the cell-intrinsic antiviral response (Rice et al., PMID: 19525956).
The described autosomal recessive SAMHD1 phenotype is considered to be a form of type 1 interferonopathy, which is defined as a condition in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO:0700260). These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with biallelic variants in SAMHD1 can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease.
Twenty variants (missense, frameshift) that have been reported in 10 probands in 3 publications (PMIDs: 20358604, 20653736, 19525956) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity thought to be to be loss of function. This gene-disease relationship is also supported by experimental evidence (model system studies, PMID: 36949945). One study demonstrated that homozygous mutant zebrafish larvae possess a number of neurological phenotypes, exemplified by variable, but increased expression of several ISGs in the head region, a significant increase in brain cell death, microcephaly and locomotion deficits align with human phenotypes. In summary, there is definitive evidence supporting the relationship between SAMHD1 and autosomal recessive SAMHD1-related type 1 interferonopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date April 29, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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