Heterozygous variants in the Sirtuin-1 (SIRT1) gene were first reported in association with monogenic type 1 diabetes (T1D) in humans in 2013 by Biason-Lauber et al. (PMID: 23473037). The SIRT p.L107P was observed in a family to segregate in an autosomal dominant manner with T1D/autoimmune diabetes and inflammatory bowel disease (IBD). SIRT1’s role in neuronal survival, oxidative stress, and mitochondrial function (PMID: 40120944) suggest its variants could contribute to neurodegenerative diseases, but such associations have not been reported in humans. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found only a single disease entity, T1D, asserted in relation to SIRT1, and no lumping or splitting was required. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
So far, only one missense variant, p.L107P, has been reported in association with T1D in a large family (PMID: 23473037) that underwent genome-wide linkage analysis followed by targeted and candidate gene sequencing (0.5 points). The published LOD score was 2.4 but was based on 5 instances of segregation of the variant with autoimmune disease (4 with T1D and 1 with ulcerative colitis) and 16 segregations of the reference allele with no autoimmune disease. There were 3 non-proband segregations of the variant with T1D, which was insufficient for calculating a LOD score based on the ClinGen SOP; therefore, 0 points were awarded for segregation. Family members without the variant in the reported family were healthy, with normal insulin secretion and action, except for two individuals who displayed features typical of type 2 diabetes and no autoimmunity. Thus, the genetic evidence reached a total of only 0.5 points.
The proposed disease mechanism is reduced anti-inflammatory function of sirtuin-1 based on increased cytokine expression in insulin-producing MIN6 cells transfected with the p.L107P variant compared with wildtype (0.5 points), bringing the total experimental evidence score to 0.5. The combined total score for genetic and experimental evidence is 1.0.
In summary, there is limited evidence supporting the relationship between SIRT1 and autosomal dominant T1D/autoimmune disease, primarily T1D. More evidence is needed to firmly establish this gene-disease relationship; the total score (1.0) falls within the limited range. The lack of genetic evidence outside a single publication remains a major limitation.
This classification was approved by the ClinGen Monogenic Diabetes Expert Panel on March 26, 2025 (SOP Version 11).
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