FLNB – Spondylocarpotarsal Synostosis Syndrome

Spondylocarpotarsal synostosis syndrome (SCT; MONDO:0010094) is an autosomal recessive skeletal dysplasia characterized by short stature, progressive fusion of vertebrae, and coalition of carpals and tarsals. Biallelic loss-of-function variants in FLNB are established causes of SCT, with over 30 patients described worldwide.

The inheritance is autosomal recessive with homozygous or compound heterozygous FLNB variants segregating fully in consanguineous and non-consanguineous families. Thirty-two probands from at least 15 unrelated families have been reported with SCT due to FLNB variants (PMID:29566257; PMID:33916386).

Case series have identified FLNB variant classes including frameshift (e.g., c.7621dup (p.Ser2542LeuTer82)), nonsense (c.220C>T (p.Gln74Ter)), splice-site, and intragenic deletions (e.g., c.3127-353_4223-1835del) (PMID:28145000; PMID:37781000; PMID:33916386). All reported variants are absent from control databases and segregate fully with disease.

Segregation analyses in consanguineous pedigrees confirm complete co-segregation of homozygous FLNB loss-of-function variants with SCT phenotype (e.g., p.Gln74Ter in three affected siblings) (PMID:37781000). Intragenic deletions and frameshift mutations lead to truncated FLNB or nonsense-mediated decay.

Functional studies demonstrate that frameshift variants disrupting the C-terminal dimerization domain (c.7621dup (p.Ser2542LeuTer82)) abolish FLNB dimer formation, reduce protein levels, and cause Golgi accumulation in HEK293T cells, confirming loss-of-function (PMID:28145000). In vivo evidence from Flnb knockout models recapitulates vertebral fusions seen in human SCT.

No conflicting evidence has been reported. FLNB-associated SCT displays phenotypic consistency across reports, with common features including scoliosis, hyperlordosis, and disproportionate short stature.

Collectively, these data support haploinsufficiency as the pathogenic mechanism. Comprehensive genetic testing for FLNB coding and structural variants is recommended for diagnostic evaluation of SCT. Due to autosomal recessive inheritance, carrier screening and genetic counselling are advised in at-risk families.

Key Take-home: Identification of biallelic FLNB loss-of-function variants provides a definitive molecular diagnosis for SCT and guides recurrence risk assessment.

References

• Human Mutation • 2017 • Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies. PMID:28145000
• The Yale journal of biology and medicine • 2023 • A Stop-gain Variant c.220C>T (p.(Gln74)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family.* PMID:37781000
• Clinical Genetics • 2018 • Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB. PMID:29566257
• Genes • 2021 • Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome. PMID:33916386

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