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This summary reviews the association between FBLIM1 (HGNC:24686) and chronic recurrent multifocal osteomyelitis (CRMO, MONDO_0009813). CRMO is a rare, pediatric autoinflammatory disease characterized by sterile osteomyelitis and bone pain, sometimes associated with psoriasis or inflammatory bowel disease. Primary evidence comes from a study identifying biallelic mutations in FBLIM1 in two unrelated probands from consanguineous families (PMID:28301468). In one case, a homozygous coding mutation affecting the filamin-binding domain was detected, whereas the second case revealed a novel frameshift mutation along with a rare regulatory variant. These findings, though arising from a limited number of cases, provide initial clues that disruption of FBLIM1 may disturb bone remodeling and inflammatory regulation. The evidence is bolstered by cellular assays showing that the regulatory variant ablates enhancer activity in SaOS2 cells, and murine microarray data revealing a dramatic downregulation of Fblim1 in a CRMO model. This integrated evidence supports FBLIM1 as a potential contributor to the pathogenesis of CRMO.
Genetic evidence indicates an autosomal recessive inheritance pattern. Affected individuals were identified in settings of consanguinity, suggesting that biallelic loss‐of‐function mutations lead to disease. Although detailed segregation data are sparse—with no additional affected relatives reported—the recurrence of the mutation in the filamin-binding domain along with a distinct frameshift mutation reinforces the causative role through allele dosage effects. For example, one reported variant meeting HGVS requirements is c.701_702del (p.Lys234ArgfsTer15), which is consistent with a deleterious frameshift change. The limited number of such probands constrains the strength of the genetic evidence, though the data are consistent with recessive inheritance.
Functional studies further substantiate the disease association. In a murine CRMO model, Fblim1 was found to be the most differentially expressed gene with more than a 20-fold reduction in expression, providing a critical link to the disease phenotype (PMID:28301468). In vitro, enhancer assays performed in SaOS2 cells demonstrated that the regulatory mutation completely abrogated enhancer activity, offering a plausible cellular mechanism through which FBLIM1 disruption could facilitate chronic inflammation and abnormal bone remodeling. These experiments not only underline the biological relevance of FBLIM1 but also highlight the importance of integrating experimental data with genetic findings to understand the underlying pathophysiology.
Overall, the current gene-disease association for FBLIM1 in CRMO is classified as Limited according to ClinGen criteria. This categorization reflects the identification of only two independent probands, modest segregation data, and experimental corroboration based on in vitro and murine studies (PMID:28301468). While these findings offer a credible basis for implicating FBLIM1 in CRMO, further replication in larger cohorts and additional segregation analyses are needed before a stronger classification can be warranted.
From a diagnostic perspective, even preliminary evidence linking FBLIM1 variants to CRMO should encourage the inclusion of this gene in genetic testing panels for patients with unexplained sterile osteomyelitis. The detection of variants such as the frameshift change c.701_702del (p.Lys234ArgfsTer15) may facilitate early diagnosis, prompt genetic counseling, and guide patient management in the context of a complex autoinflammatory disorder. Adopting such a genetic approach will be beneficial particularly in populations with a high prevalence of consanguinity.
In summary, although the available evidence is limited, the convergence of genetic data and functional assays provides a compelling narrative that FBLIM1 disruption plays a role in the pathogenesis of CRMO. Key take‑home sentence: Incorporating FBLIM1 testing into the diagnostic workup for CRMO could improve clinical decision-making and pave the way for tailored therapeutic strategies.
Gene–Disease AssociationLimitedTwo independent probands with biallelic FBLIM1 mutations in consanguineous families and supporting functional data from enhancer assays and murine studies (PMID:28301468). Genetic EvidenceLimitedRecessive inheritance supported by a homozygous coding mutation and a novel frameshift mutation with a regulatory variant in two unrelated probands; however, segregation data are minimal. Functional EvidenceModerateFunctional assays in a CRMO murine model and SaOS2 cell enhancer studies demonstrated significant downregulation of FBLIM1 and loss of enhancer activity, providing biological plausibility. |