TNFSF11 gene is located on chromosome 13 at 13q14.11 and encodes the tumor necrosis factor ligand superfamily member 11 protein which plays a crucial role in several biological processes, particularly in bone remodeling, immune function, and the formation of mammary glands during pregnancy (PMIDs: 37893470, 32850393). One disease assertion has been reported in association with this gene: osteopetrosis, autosomal recessive 2 (MIM:259710, MONDO:0009816). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in molecular mechanism, phenotypic variability, and inheritance pattern. Therefore the following disease entity has been lumped into one entity: TNFSF11 and TNFSF11-related osteopetrosis (MONDO: ID requested).
TNFSF11 was first reported in connection with TNFSF11-related osteopetrosis in 2007 (Sobacchi et al. 2007 PMID: 17632511). Patients with this disease may present with optic atrophy, blindness, cranial nerve involvement, hydrocephalus, severe cerebral bulbar deterioration, severe growth inhibition, severely impaired and/or delayed dentition with chronic parotid/mandibular abscess, short stature, hepatosplenomegaly, anemia, hypocalcemic seizure, and hypocalcemia (PMID: 34056870).
Six variants (2 frameshifts, 2 missense, 1 deletion, 1 splice site) reported in four publications have been included in this curation (PIMDs: 39011244, 34056870, 23762088, 17632511). This gene-disease relationship is also supported by two non-human model organisms (PMIDs: 10984520, 22068587), protein interaction (PMID: 22664871), biochemical function (PMID: 32850393), skeletal and extraskeletal expression (PMID: 9568710), and rescue in a non-human model organism (PMID: 23762088).
In summary, there is definitive evidence supporting the relationship between TNFSF11 and TNFSF11-related osteopetrosis. The classification was approved by the ClinGen Skeletal Disorders GCEP on meeting date 12/02/2024 (SOP Version 11)
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