Non-Syndromic Cleft Palate and Transverse Limb Deficiency Segregating in a Family of Dogs

Abstract

Oro-facial clefts are one of the most common birth defects in humans, most are non-syndromic, and few have established molecular diagnoses. Here we report the morphology and genetic transmission of isolated cleft palate in a naturally occurring dog model. Palate morphology was evaluated grossly, by microcomputed tomography, and by histologic examination of serial coronal sections. In repeated matings of a clinically normal sire/dam pair, 18% (12/68) of live-born pups had full-length cleft of the secondary palate with no other abnormalities. At the gestational stage of normal palate fusion, palate shelves of affected fetuses were above the tongue but did not meet at midline. Mandibles were normal, and oral epithelium and periderm were intact. Genetic transmission was determined in experimental backcross matings of surgically repaired affected dogs with a normal parent, which produced 20 cleft, 11 male and 9 female, and 24 normal-palate pups. Furthermore, all offspring of matings between affected dogs had cleft palate. These data were as expected under the hypothesis of autosomal recessive transmission of the cleft palate trait ([1 df, N = 44] Χ2 = 0.36, p = 0.55). About half of cleft offspring produced in backcross matings of which the dam had cleft palate, also exhibited various transverse limb deficiencies. No limb deficiencies occurred in backcross offspring of a dam with normal palate, suggesting a possible maternal effect. This dog family constitutes a large animal model of non-syndromic isolated cleft palate coincident with developmental limb deficiency.