Clinical and Genetic Characterization of Polydactyly in Selected Families

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 (AD) or recessive (AR) form and has syndromic and non syndromic types. Non-syndromic types are preaxial polydactyly (PPD) refers to an extra digit adjacent to the first digit on a radial side of the hand (thumb) or on a tibial side of the foot (toe). Postaxial polydactyly (PAP) refers to one or more additional digits at the ulnar/fibular side of the hand/foot. EVC syndrome is a type of Syndromic polydactyly and its characteristic features are post-axial polydactyly, leukonychia nails, dwarfism, dental and oral signs. Less variable symptoms of this syndromic polydactyly are post-axial polydactyly of feet and development retardation. The current study investigated two consanguineous Pakistani families at clinical and genetic levels. Family A showed an autosomal recessive inheritance pattern of the disorder in the consanguineous family. Whole exome sequencing was performed on the affected members and several filters were applied to the exome data focused on pathogenic variants linked to non-syndromic polydactyly. Out of four selected variants, only two underwent segregation analysis but none of them segregated with the disorder. Therefore, it is recommended to conduct a segregation analysis with the other two variants. Similarly, Family B was placed under the category of EVC syndrome. It showed an autosomal recessive inheritance pattern of the disorder. A search for the causative genes and variants was carried out using microsatellite markers to establish linkage in the family. Genotyping was performed using polymorphic microsatellite markers linked to eight candidate genes, including GLI1 (12q13.3), GLI3 (7p14.1), DYNC2H1 (11q22.3), IQCE (7p22.3), EVC1 (4p16.2), EVC2 (4p16.2), FAM92A (8q22.1), MIPOL1 (14q13.3). Genotyping failed to establish a linkage in the family to the tested markers. This indicated the involvement of novel genes causing the recorded phenotypes in the family.