Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

• Published in: Journal of genetics and genomics 2024-02, Vol.51 (2), p.222-229
• Main Authors: Huang, Wenbin, Zhang, Shiying, Lin, Jiuxiang, Ding, Yi, Jiang, Nan, Zhang, Jieni, Zhao, Huaxiang, Chen, Feng
• Format: Article
• Language: English
• Subjects: Actin filament; Animals; Brain - abnormalities; Cleft Lip - genetics; Cleft palate; Cleft Palate - genetics; Filamin B; Filamins - genetics; FLNB; Humans; Knockout mouse; Loss-of-function mutation; Mammals; Mice; Mutation; Orofacial clefts
• ISSN: 1673-8527
• DOI: 10.1016/j.jgg.2023.03.012

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb−/− embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.