A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity

Background: Congenital anomalies of the knee are a spectrum of rare disorders with wide clinical and genetic variability, which are mainly due to the complex processes underlying knee development. Despite progresses in understanding pathomechanisms and associated genes, many patients remain undiagnosed. Objective: To uncover the genetic bases of a congenital patellar dislocation affecting multiple family members with variable severity. Methods: We performed ES in the proband and his father, both showing bilateral patellar dislocation, his sister with a milder similar condition, and his unaffected mother. Sanger sequencing was then performed in the proband’s brother and paternal aunt, both affected as well. Results: ES and Sanger sequencing identified the presence of the novel heterozygous frameshift mutation c.735delT in the TBX4 gene in all affected family members. TBX4 is associated with autosomal dominant ischio-coxo-podo-patellar syndrome with/without pulmonary arterial hypertension (ICPPS, #147891), reaching a diagnosis in the family. Intrafamilial clinical heterogeneity suggests that other factors might be involved, such as additional variants in TBX4 or in other modifier genes. Interestingly, we identified three additional variants in the TBX4 gene in the proband only, whose phenotype is more severe. Despite being classified as benign, one of these variants is predicted to disrupt a splicing protein binding site, and may therefore affect TBX4 alternative splicing, accounting for the more severe phenotype of the proband. Conclusion: We expand and further delineate the genotypic and phenotypic spectrum of ICPPS. Further studies are necessary to shed light on the potential effect of this variant and on the variable phenotypic expressivity of TBX4-related phenotypes.