Unraveling the Genetic Basis of Congenital Limb Anomalies in Eight Families

Limb abnormalities are the second most frequent birth defects seen in infants, after congenital heart disease. Over the past 150 years, more than 50 classifications for limb malformations based on morphology and osseous anatomy have been presented. The goal of the current study is to investigate the genetic basis of congenital limb abnormalities in the Pakistani population. Eight families, presenting different forms of limb anomalies, including syndactyly, polydactyly, synpolydactyly, and ectrodactyly in an autosomal dominant manner, were genetically and clinically investigated. Whole exome sequencing followed by Sanger sequencing was used to search for the disease-causing variants. Sequence analysis revealed five novel variants in LMBR1, GJA1, HOXD13, and TP63 and three previously reported variants in GJA1 and HOXD13. This study expanded the mutation spectrum in the identified genes and will also help in improved diagnosis of the limb anomalies in the local population.