Submission Details

Autosomal dominant

02/25/2019

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.

21204240 19525956 29670289