The keeshond defect in cardiac conotruncal development is oligogenic.
Earlier studies in the keeshond breed of dogs established that isolated conotruncal defects (CTDs) are a group of genetically and embryologically related cardiac malformations, including sub-clinical defects of the conal septum, conal ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus. The same spectrum occurs in some human families. In both species, inheritance of non-syndromic CTDs is usually complex and multifactorial inheritance has been assumed. Previous studies in the keeshond suggested that susceptibility to CTD is an autosomal recessive trait, with alleles at modifying loci affecting severity. Here we report results of a genome-wide scan for CTD linked loci in a keeshond x beagle F1 backcross pedigree in which 46 of 101 offspring had CTDs. Two-point linkage analysis identified regions of suggestive linkage on each of three chromosomes CFA2, CFA9, and CFA15. No single locus accounted for segregation of CTDs in the pedigree, ruling out a single autosomal susceptibility locus. Multipoint analysis with Genehunter resulted in a corrected LOD score of 3.7 at the locus on CFA9 and supported linkage to the loci on CFA2 and CFA15 (LOD scores of 2.71 and 3.03). Genehunter Twolocus analysis suggested that CTD-predisposing alleles of these three loci are necessary, at least in pairs, to produce CTD. The canine CTD-linked chromosome regions are orthologous to human regions HSA5q11-13, HSA5q31, HSA17q11-24, and HSA4q31. We excluded from the linked regions in the dog, a number of genes known to have a role in the etiology of CTDs and predict that continuing studies will identify CTD-predisposing genes not previously recognized.
Werner
Petra
P
Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancy Street, Philadelphia, PA 19104-6010, USA. pwerner@vet.upenn.edu
Raducha
Michael G
MG
Prociuk
Ulana
U
Ostrander
Elaine A
EA
Spielman
Richard S
RS
Kirkness
Ewen F
EF
Patterson
Donald F
DF
Henthorn
Paula S
PS
D000818:Animals; D002874:Chromosome Mapping; D004285:Dogs; D005808:Genes, Recessive; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000235:genetics*; D008126:Lod Score; D020412:Multifactorial Inheritance