The TLR7 (Toll-like receptor 7) gene encodes a viral RNA sensor (PMID:35477763) that plays a key role in the recognition of pathogen-derived single-stranded RNA (ssRNA), which is integral to the innate immune response to viral infections. TLR7 can also recognize self-derived ssRNA, which may underlie the association of gain-of-function mutations in this gene with systemic lupus erythematosus (SLE) (PMID:38324161). TLR7 was first reported in relation to X-linked dominant SLE in 2022 (Brown et al., PMID:35477763).
Genetic evidence reviewed in the curation of this gene-disease relationship included 6 probands with 4 unique heterozygous variants. The molecular mechanism of disease is gain of function: only rare missense variants with in vitro functional evidence of gain of function have been reported (PMID: 35477763, 38753439, 38324161). No loss of function variants have been reported in individuals with SLE (ClinVar, literature review). Genetic evidence that was not scored include one study that reported association of TLR7 copy number gain with SLE (PMID:20525845); however, this finding has not been replicated. In addition, common variants in TLR7 are associated with increased risk of SLE and/or SLE-related phenotypes in cases compared to healthy controls (PMID: 33272962, 20733074, 36439744, 33650302), but these associations have not been replicated in genome-wide association studies.
The gene-disease relationship is also supported by experimental evidence including biochemical function, function alterations and animal model data. SLE patients with TLR7 variants display increased NFkB activity and B cell alterations typical for lupus (PMID: 38753439, 38324161, 35477763). A knock-in animal model of the p.Y264H variant recapitulates lupus-like phenotypes in mice (PMID: 35477763).
In summary, there is moderate evidence supporting the relationship between TLR7 and X-linked dominant systemic lupus erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date October 11, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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