Identification of a Mutation for Nonsyndromic Cleft Palate in the NSDTR

Orofacial clefts are the most commonly occurring craniofacial birth defects in humans.  It is not surprising that dogs, which intimately share our environment and are developmentally similar, have naturally occurring orofacial clefts. A breed of dog with a reported high incidence of cleft palate is the Nova Scotia Duck Tolling Retriever (NSDTR).  Genome –wide association of 14 cleft palate cases and 73 controls in this breed identified an associated region on CFA14 (p-raw =4.664 x10 -15, p-genome=1.0 x 10-5) with a 5.1Mb haplotype underlying the association.  Genotyping and linkage analysis (LOD=3.18) across the region gave results consistent with an autosomal recessive mode of inheritance for cleft palate.  Sequencing of positional candidate genes within the 5.1Mb interval identified a putative causative mutation for cleft palate in a gene involved in craniofacial development. PCR genotyping of 284 unaffected dogs from 69 breeds failed to identify a single copy of the mutation.  35 nonsyndromic cleft palate affected dogs from 20 other breeds were also genotyped and did not have the mutation.