Brachydactyly type A1 (BDA1): Identification and characterization of the genes involved

Brachydactyly type A1 (BDA1) belongs to a group of rare, congenital disorders whereby normal bone development and patterning is adversely affected, leading to shortened and malformed digits. BDA1 has the unique feature of being the first human trait described in terms of autosomal dominant Mendelian inheritance. In 2001, missense mutations within the Indian Hedgehog (IHH) gene, specifically codons 95, 100 and 131, were identified in three unrelated families affected with BDA1. Our laboratory recently identified linkage of BDA1 to a second locus on chromosome 5p13.3 in a large Canadian kindred. The critical region on chromosome 5p has been refined to 7 cM by genotype and haplotype analysis of family members. One goal of this thesis was to further reduce the 7 cM critical region, which was successful, given that a 40 kb region was eliminated. Throughout the early 1900s, William Farabee and Harry Drinkwater identified, and subsequently detailed, several families affected with BDA1 (Farabee, 1903 and Drinkwater, 1907/8, 1912, 1915). At the time of his reports, Drinkwater proposed that the Pennsylvania family, identified by Farabee, may be related to his kindreds. For years the question of whether the two Drinkwater families and the Farabee family were related through a common founder remained a mystery. This thesis provides evidence and support for a common ancestry between Drinkwater's two BDA1 families and the BDA1 family of Farabee's. In addition, this thesis also investigates IHH's role in BDA1 as numerous BDA1 families underwent IHH mutational analysis in the search for novel IHH mutations leading to BDA1