Whole-exome sequencing identifies a novel insertion in an Ontario family with brachydactyly type A1

Isolated brachydactyly is an umbrella term describing disproportionally shortened fingers and toes, often following an autosomal dominant mode of inheritance. Various forms of brachydactyly have been characterized and several causative genes have been found, but many types remain genetically undefined. We describe an Ontario family with mild brachydactyly in which whole-exome sequencing identified a novel variant for brachydactyly type A1 (exon 1, c.285_287dupGAA, p.Glu95_Asn96insLys) in the Indian hedgehog ( IHH ) gene. This rare variant co-segregated with affected status in the pedigree and was associated with (1) shortened middle phalange length by 21.1% ( p < 0.001); (2) shortened palm length by 13.8% ( p < 0.01); (3) reduced digit-palm ratio by 6.8% ( p < 0.03); and (4) reduced stature by 9.5% ( p < 0.001). We report the first IHH in-frame insertion causing brachydactyly type A1