FLNB – Boomerang dysplasia

Boomerang dysplasia is a perinatal lethal osteochondrodysplasia characterized by absence or underossification of limb bones and vertebral elements and a boomerang-shaped appearance of the long tubular bones. The condition results from pathogenic variants in FLNB, encoding the actin-binding cytoskeletal protein filamin B, which is essential for vertebral segmentation and endochondral ossification (Boomerang dysplasia).

ClinGen clinical validity for FLNB–Boomerang dysplasia is classified as Strong. This is supported by the identification of missense FLNB variants in two unrelated probands ([PMID:15994868]) and an independent case report ([PMID:22354125]) with concordant lethal phenotypes and characteristic radiological findings. Experimental studies corroborate these findings by demonstrating consistent pathogenetic mechanisms in cellular and biochemical assays.

The inheritance of Boomerang dysplasia is autosomal dominant, often arising de novo with no reported familial segregation beyond probands. To date, three unrelated individuals have been reported: two with substitutions in the calponin-homology 2 domain (c.703T>C (p.Ser235Pro), c.512T>G (p.Leu171Arg)) and one with a third distinct ACTB-binding domain variant. No additional affected relatives have been documented, consistent with sporadic occurrence and severe perinatal lethality.

All reported disease-causing FLNB alleles in Boomerang dysplasia are missense variants clustered in the N-terminal actin-binding domain (ABD), supporting a gain-of-function mechanism. Notably, c.703T>C (p.Ser235Pro) and c.512T>G (p.Leu171Arg) disrupt the second calponin-homology domain of the ABD and are fully penetrant in the perinatal period.

Functional evidence is Moderate. Biochemical assays of FLNB ABD mutants demonstrate enhanced F-actin binding affinity and preserved ABD structure ([PMID:19505475]). Cellular studies show that ABD mutations form cytoplasmic focal accumulations correlating with disease severity and impair cytoskeletal organization ([PMID:22190451]). These data align with the clinical phenotype of nonossification and skeletal disorganization.

Integration of genetic and experimental data supports a gain-of-function mechanism by which FLNB missense variants in the ABD lead to aberrant actin cross-linking and fatal skeletal dysplasia. There are no conflicting reports disputing FLNB’s role in Boomerang dysplasia. Further studies may explore targeted therapies to modulate actin binding in utero. Key take-home: FLNB missense variants in the actin-binding domain are strongly diagnostic for perinatal lethal Boomerang dysplasia.

References

• Fetal diagnosis and therapy • 2012 • A case of boomerang dysplasia with a novel causative mutation in filamin B: identification of typical imaging findings on ultrasonography and 3D-CT imaging. PMID:22354125
• Journal of medical genetics • 2005 • Mutations in FLNB cause boomerang dysplasia. PMID:15994868
• Journal of molecular biology • 2009 • Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains. PMID:19505475
• Human mutation • 2012 • Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity. PMID:22190451

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