Identification and Functional Verification of Variants Associated With Clubfoot and Arthrogrypotic Hand Deformation...

Clubfoot, or talipes equinovarus (TEV), is an autosomal dominant foot malformation characterized by a variable clinical picture, ranging from mild to severe deformity. While its genetic basis has been partly elucidated, the underlying molecular mechanisms remain incompletely understood.

We investigated a five-generation Polish family presenting autosomal dominant clubfoot associated with arthrogrypotic hand deformation. Genotyping was performed to identify variants co-segregating with the phenotype. Aberrant splicing effects were assessed in the proband's sample, and functional validation was carried out in zebrafish.

Two variants were identified that segregated with the phenotype. The first, TMEM256 c.118-4dup, is an intronic duplication resulting in aberrant splicing. The pathogenicity of the misspliced TMEM256 products was confirmed in zebrafish. The second variant, MYH3 c.1123G>A;p.(Glu375Lys), is a previously reported missense change potentially explaining the arthrogryposis-like hand deformations in the affected family members.

Our findings reveal TMEM256 as a potential novel candidate gene for clubfoot and highlight the contribution of MYH3 variants to the broader clinical spectrum observed. These findings contribute to understanding the genetic complexity underlying clubfoot, providing unique insights into potential novel candidate gene and pathways involved in this condition.