No therapy for mtDNA depletion disorders currently exists with treatment mainly consisting of supportive care. Intriguingly, we found that rare variants within SAMHD1 were associated with increased levels of mtDNA-CN. SAMHD1 is a multifaceted enzyme with various functions including tumour suppression through DNA repair activity and maintenance of steady-state intracellular dNTP levels, which has been involved in HIV-1 replication .
Rare homozygous and compound heterozygous loss-of-function mutations in SAMHD1 result in an immune encephalopathy known as Aicardi Goutiere’s syndrome. Imbalanced intracellular dNTP pools and chronic DNA damage cause persistent elevations in interferon alpha thus mimicking a prolonged response to HIV-1 infection.
While Aicardi Goutiere’s syndrome is a severe recessive genetic disorder, case reports of SAMHD1-related disease often describe heterozygous parents and siblings as being unaffected or with milder disease.
- In the UKBiobank, the vast majority (99.4%) of individuals possessing SAMHD1
- mutations were heterozygote carriers, who had a two-fold increased risk of breast cancer.
- Such findings may have important clinical implications for genetic screening.
- heterozygous SAMHD1 mutations may be an overlooked risk factor for breast cancer
- considering that ∼1 in 130 UKBiobank participants possessed a genetic mutation conferring two-fold elevated risk.
Notably, while SAMHD1 mutations have been described previously to be associated with various cancersµµ, this gene is not routinely screened nor part of targeted gene panels outside the context of neurological disorders