The Spondylocarpotarsal Synostosis Syndrome Case with Ventricular Septal Defect Caused by a Homozygous Frameshift Variation in FLNB

Abstract

Spondylocarpotarsal synostosis syndrome (SCT) (OMIM: 272460), an autosomal recessive disorder, is characterized by block vertebrae, carpal–tarsal synostosis, and disproportionate short stature. The clinical features of SCT include dysmorphic facial traits, cleft palate, hypoplastic tooth enamel, brachydactyly, clinodactyly, limited joint movement, and mixed hearing loss. SCT is associated with biallelic nonsense and frameshift pathogenic variants in the FLNB gene. An 8-year-old patient was referred with suspected skeletal dysplasia. The patient presented with short stature, scoliosis, carpal–tarsal synostosis, and ventricular septal defect (VSD). Clinical exome sequence analysis revealed a homozygous frameshift variation in the FLNB gene (c.219_222dup p.Met75Profs*17). No other pathogenic variations in genes related to VSD were found. This study aims to discuss novel clinical findings related to the genotype–phenotype association. To the best of our knowledge, this is the first reported case of SCT with VSD.

Keywords

filamin B - FLNB - SCT - VSD - carpal–tarsal synostosis

Ethical Statement

Written informed consent was obtained for all studied individuals and for the use of photos. Clinical examination and genetic analysis were performed for routine clinical investigation.

Publication History

Received: 18 October 2023

Accepted: 11 September 2024

Article published online:
23 October 2024

• References

• 1 Langer Jr LO, Gorlin RJ, Donnai D, Hamel BC, Clericuzio C. Spondylocarpotarsal synostosis syndrome (with or without unilateral unsegmented bar). Am J Med Genet 1994; 51 (01) 1-8
• 2 Cameron-Christie SR, Wells CF, Simon M. et al. Recessive spondylocarpotarsal synostosis syndrome due to compound heterozygosity for variants in MYH3. Am J Hum Genet 2019; 105 (03) 669
• 3 Krakow D, Robertson SP, King LM. et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 2004; 36 (04) 405-410
• 4 Bicknell LS, Farrington-Rock C, Shafeghati Y. et al. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet 2007; 44 (02) 89-98
• 5 Salian S, Shukla A, Shah H. et al. Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB. Clin Genet 2018; 94 (01) 159-164
• 6 Fukushima K, Parthasarathy P, Wade EM. et al. Intragenic deletions in FLNB are part of the mutational spectrum causing spondylocarpotarsal synostosis syndrome. Genes (Basel) 2021; 12 (04) 528
• 7 Yasin S, Makitie O, Naz S. Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report. BMC Musculoskelet Disord 2021; 22 (01) 31
• 8 Harrison SM, Biesecker LG, Rehm HL. Overview of specifications to the ACMG/AMP variant interpretation guidelines. Curr Protoc Hum Genet 2019; 103 (01) e93
• 9 Robertson S. FLNB disorders. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW. , et al., eds. GeneReviews. Seattle (WA);: 1993
• 10 Farrington-Rock C, Kirilova V, Dillard-Telm L. et al. Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome. Hum Mol Genet 2008; 17 (05) 631-641
• 11 Mitter D, Krakow D, Farrington-Rock C, Meinecke P. Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father. Am J Med Genet A 2008; 146A [phone]
• 12 Yang CF, Wang CH, Siong H'ng W. et al. Filamin B loss-of-function mutation in dimerization domain causes autosomal-recessive spondylocarpotarsal synostosis syndrome with rib anomalies. Hum Mutat 2017; 38 (05) 540-547
• 13 Stossel TP, Condeelis J, Cooley L. et al. Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol 2001; 2 (02) 138-145
• 14 Zieba J, Forlenza KN, Khatra JS. et al. TGFβ and BMP dependent cell fate changes due to loss of filamin B produces disc degeneration and progressive vertebral fusions. PLoS Genet 2016; 12 (03) e1005936
• 15 Lu J, Lian G, Lenkinski R. et al. Filamin B mutations cause chondrocyte defects in skeletal development. Hum Mol Genet 2007; 16 (14) 1661-1675
• 16 Shimizu H, Watanabe S, Kinoshita A. et al. Identification of a homozygous frameshift variant in RFLNA in a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome. J Hum Genet 2019; 64 (05) 467-471
• 17 Sousa SB, Baujat G, Abadie V. et al. Postnatal growth retardation, facial dysmorphism, spondylocarpal synostosis, cardiac defect, and inner ear malformation (cardiospondylocarpofacial syndrome?)–a distinct syndrome?. Am J Med Genet A 2010; 152A [phone]