Homozygosity for a Canonical FLNB Splice-Donor Variant and a Co-Inherited Missense Variant on a Single Haplotype in Spondylocarpotarsal Synostosis Syndrome: Neither Variant Can Receive Allelic Evidence Independently

Spondylocarpotarsal synostosis syndrome (SCT) is an autosomal recessive skeletal dysplasia caused by biallelic loss-of-function FLNB variants, which include nonsense, frameshift, canonical splice-site, and structural alleles. We report a girl aged 6 years 8 months, born to first-cousin parents, with disproportionate short stature and progressive scoliosis, evaluated clinically, radiologically and by exome sequencing. Two rare FLNB variants were identified: the canonical splice-donor variant NM_001457.4:c.4514+1G>C and the missense variant c.6635C>T p.(Ala2212Val). Sanger sequencing showed the proband to be homozygous and each parent heterozygous for both, so the two variants lie 21,859 bp apart on one ancestral haplotype inherited from both parents. The splice-donor variant was classified as pathogenic and accounts for the phenotype. Because the missense variant is carried on the same haplotype, allelic (PM3) and phenotypic (PP4) evidence cannot be attributed to it independently, and it remains of uncertain significance; structural modelling of the buried residue Ala2212 is not functional evidence. Imaging showed multilevel vertebral and posterior-element fusion, carpal and tarsal coalition, and a major curve that progressed from 14 to 35 degrees in twelve months. In consanguineous families, homozygosity for two rare variants in one gene reflects a single haplotype, and neither variant can be credited independently.