SAMHD1

Inheritance Pattern: AR

Disease ID:MONDO:0013059

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0016820

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0013059

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0018827

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018866

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013059

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0019557

Submitter: Illumina

The SAMHD1 gene is located on chromosome 20 at 20q11.23 and encodes the SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 protein. Through its role in the replication stress response, this protein prevents the induction of interferons and inflammation by limiting the release of single-stranded DNA from stalled replication forks. In addition, its dNTPase activity functions to reduce cellular dNTP levels and restrict viral infection. The SAMHD1 gene was first reported in relation to autosomal dominant chilblain lupus in 2011 (21204240: Ravenscroft et al. 2011). The clinical data supporting this association are limited to a single unconvincing case (Ravenscroft et al. 2011), as the same variant identified in the only reported case has also been reported in a heterozygous state in at least four unaffected individuals (19525956: Rice et al. 2009; 20653736: Ramesh et al. 2010; 30275001: Haskell et al. 2018). Of note, this gene has also been implicated in Aicardi-Goutieres syndrome. This will be assessed separately. In summary, there is convincing evidence disputing the association between SAMHD1 and autosomal dominant chilblain lupus. More evidence is needed to either support or refute the role SAMHD1 plays in this disease. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotype. An assertion for an independent disease association has been made (21204240: Ravenscroft et al. 2011), but the autosomal dominant disorder of chilblain lupus has also been suggested to be a forme fruste of the primary autosomal recessive manifestation of Aicardi-Goutieres syndrome (AGS) (17357087: Rice et al. 2007; 27604406: Yarbrough et al. 2016). The phenotypes are largely distinct in that typical AGS is much more severe; however, chilblains are sometimes present in SAMHD1 AGS, and atypical AGS can result in a lupus-like phenotype. No difference in molecular mechanism has been asserted. For these reasons, we have split curations for the disease entities chilblain lupus and Aicardi-Goutieres syndrome.

Inheritance Pattern: AD

Disease ID:MONDO:0013739

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0700260

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0013059

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013059

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013059

Submitter: PanelApp Australia