Supplementary Material for: A Novel Variant in the Cyto-Tail of SMO Gene Underlying Isolated Postaxial Polydactyly

Background Polydactyly is one of the most common hereditary limb malformations, characterized by presence of additional digits in hands and/or feet. It is present either in isolated form or in combination with other features. Preaxial polydactyly with extra digit on outside of thumb or big toe, and postaxial polydactyly with extra digit on outside of little finger or little toe are the two main forms of polydactyly. Methods and Results In the present study, two unrelated consanguineous families segregating postaxial polydactyly in an autosomal recessive manner were investigated. Whole-exome sequencing (WES), followed by segregation analysis using Sanger sequencing revealed a homozygous missense variant [c.1792 G>A; p.(Gly598Arg); NM_005631.5] in the SMO in both families. Proteins SMO, PTCH, and GLI act as major components of the Sonic Hedgehog pathway, which transmits signals to embryonic cells for cellular differentiation. Homology modeling revealed that the variant in SMO may disrupt proper protein folding and interaction with other molecules. Conclusion In conclusion, our study has revealed the second direct involvement of a sequence variant in the SMO causing isolated polydactyly. This study will highlight the importance of the inclusion of the SMO gene in screening individuals presenting polydactyly in hands and feet.