FLNB-Related Disorders via the FLNB Gene

Mutations in the FLNB gene are known to cause the following skeletal abnormalities: atelosteogenesis type 1(AOI; OMIM#108720) and type 3 (AOIII; OMIM#108721); boomerang dysplasia (OMIM#112310), Larsen syndrome (OMIM#150250), and spondylocarpotarsal synostosis syndrome (OMIM#272460) (SCT). These disorders are characterized by disrupted vertebral segmentation, joint formation and endochondral ossification. SCT is a relatively mild disorder caused by mutations in FLNB, and is characterized by disproportionate short stature, fusion of the vertebral, carpal, and tarsal bones, and facial dysmorphisms. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; club feet; scoliosis and cervical kyphosis. Atelosteogenesis (AO) is chondrodysplasia characterized by hypoplasia of the midthoracic spine, distal humeri and femurs hypoplasia. AOI is a perinatal lethal condition characterized by severe short-limbed dwarfism. AOIII is relatively mild in comparison to AOI, patients can usually survive beyond the neonatal period. Boomerang dysplasia is also a perinatal lethal condition characterized by femoral bowing; some patients may have encephalocele and omphalocele (Krakow et al. Nat Genet 36(4): 405–410, 2004; Bicknell et al. J Med Genet 44(2):89–98, 2005; Farrington-Rock C et al. Hum Mutat 27(7):705–710, 2006; Bicknell et al. J Med Genet 42(7):e43, 2007 and Robertson, Stephen. GeneReviews, 2008).

Except for SCT, which is autosomal recessive, all FLNB-related disorders are inherited in an autosomal dominant manner. The majority of lethal FLNB-related disorders are caused by de novo mutations, and a few cases with low-level mosaicism have also been reported. Filamin B protein encoded by FLNB (OMIM#603381) is an actin binding protein. By binding to actin, Filamin B connects with many other proteins to form the filaments of the cytoskeleton network. It plays a key role in chondrocyte development and cartilage ossification. To date, about 80 distinctive mutations have been documented in HGMD (Human Gene Mutation Database); they are: missense (66/81); nonsense (6/81), small deletions (6/81), splicing (1/81), large deletion (1/81) and genomic rearrangement (1/81). All documented nonsense mutations are found in patients with spondylocarpotarsal synostosis syndrome (Krakow et al., 2004; Daniel et al. Hum Mutat 33(4):665-673, 2012).

Analytical sensitivity should be high, because approximately 97% of the documented FLNB mutations are point mutations and small deletions, which are expected to be detected by direct sequencing of genomic DNA. Clinical sensitivity may be high in patients diagnosed by radiology (Daniel et al. Hum Mutat 33(4):665-673, 2012).

No gross deletions/duplications have been reported in FLNB (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the FLNB gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.