Search for Disease-Causing Variants in Families with Postaxial Polydactyly Using Whole Exome Sequencing.

Abstract

Polydactyly, also known as hexadactyly or hyperdactyly, is a genetic limb disorder characterized by the presence of an extra digit. Polydactyly can be inherited in autosomal dominant or recessive form and has syndromic and non-syndromic types. Postaxial polydactyly (PAP) refers to one or more additional digits at the ulnar/fibular side of the hand/foot respectively. In the current study, the families were identified with the Non-Syndromic Postaxial Polydactyly and proceeded with the molecular and clinical analysis in order to find a potential candidate gene. Family A showing an autosomal dominant inheritance pattern in the consanguineous family was followed for WES. The WES followed by Sanger sequencing was performed to identify the potential disease-causing variant. These variants were also scrutinised by various in-silico tools. WES analysis of family A revealed a novel variant (exon 13, c.1657G>A; p.555Val>Met) of FGFR3, mapped on chromosomal position 4p16.3, in isolated bilateral PAP in lower appendages. Family B exhibits an autosomal recessive inheritance pattern in the non-consanguineous family. The WES followed by Sanger sequencing identified a novel homozygous missense mutation (c.1792G>A; p.598Gly>Arg) in exon 10 of the already reported SMO gene in non syndromic PAP. In conclusion, the present research study identified two variants that might help better understand genotype-phenotype correlation. This study will help in the understanding of the role of FGFR3 and SMO in limb deformities and will also help in the prenatal testing and genetic counselling of the affected families