Genetic Mapping and Sequence Analysis of Candidate Genes Causing Non-Syndromic Polydactyly

Abstract

Several signaling pathways, by involving large number of proteins, play important roles in development of human limbs. Disturbances in the functions of the protein encoding genes lead to result in different types of congenital limb deformities. These anomalies occur either as an isolated malformation of the hands/feet or as a part of complex syndrome. In humans, polydactyly is the most frequently observed congenital hand and feet malformation. Major type of non-syndromic forms of polydactyly is classified into pre-axial, postaxial and central type polydactyly. In the present study, four consanguineous families (A, B, C, D) segregating polydactyly were recruited from different remote regions of the country. Pedigree sketches showed segregation of the disorder in three families (A-C) followed autosomal recessive mode of inheritance. Family D, on the other hand, showed autosomal dominant mode of inheritance. Linkage in the family A-C was searched by typing microsatellite markers linked to several candidate genes involved in causing polydactyly. Analysis of the haplotypes, constructed from the typed markers, however excluded the families from linkage to the tested genes. Sequencing of two candidate genes (GLJ3, ZRS/SHH) in affected and unaffected members revealed a heterozygous variant (c.1 034 + 182 T>C) in enhancer sequences located in intron 5 of the LMBRI. The variant is predicted to affect the expression of the LMBRI leading to autopod anomalies. The present study will not only be helpful in identifying additional genes involved in human limb development but also facilitate prenatal diagnosis and genetic counseling of the families showing polydactyly features.