Genetic mutations in SAMHD1 (SAM domain- and HD domain-containing protein 1) are responsible for two types of autoinflammatory interferonopathies: autosomal dominant familial chilblain lupus and recessive Aicardi-Goutières syndrome. Somatic mutations in various genes cause adult-onset autoinflammatory diseases, but none involving SAMHD1 have been reported. Here, we report a sporadic case of late-onset chilblain lupus with a novel single-nucleotide variant of SAMHD1 and a somatic large deletion in chromosome 20.
A 76-year-old man presented with widespread erythema and deforming ulcers of the fingers and auricles, starting at age 70 and worsening in winter. Negative autoantibodies and an elevated interferon score suggested autoinflammatory interferonopathy. Targeted sequencing identified a novel single-nucleotide variant (SNV) in SAMHD1 (PolyPhen-2 score: 1.000) with a variant allele frequency of 60%, along with a reduced read depth in SAMHD1 (75%) in blood, suggesting a somatic deletion. Whole-genome sequencing identified a large deletion in chr20, including SAMHD1 on the SNV-free allele, which was absent in oral mucosa. The deletion rates in monocytes, neutrophils, B cells, and T cells were 81%, 54%, 53%, and 0%, respectively. Given its frequent occurrence in myeloid malignancies, del(20q) likely contributed to clonal expansion. These results suggest that the late-onset chilblain lupus can result from biallelic loss-of-function mutations in SAMHD1 in leukocytes.
We detected a novel SAMHD1 SNV and a somatic large deletion in leukocytes in a case of late-onset chilblain lupus. Although functional analyses are ongoing, these findings suggest that leukocyte dysfunction alone may be sufficient to trigger chilblain lupus. Furthermore, this case suggests the importance of analyzing somatic mutations in late-onset chilblain lupus or lupus erythematosus.
