An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome

Abstract

In flat-faced dog breeds, air resistance caused by skull conformation is believed to be a major determinant of Brachycephalic Obstructive Airway Syndrome (BOAS). The clinical presentation of BOAS is heterogeneous, suggesting determinants independent of skull conformation contribute to airway disease. Norwich Terriers, a mesocephalic breed, are predisposed to Upper Airway Syndrome (UAS), a disease whose pathological features overlap with BOAS. Our health screening clinic examined and scored the airways of 401 Norwich terriers by laryngoscopy. Genome-wide association analyses of UAS-related pathologies revealed a genetic association on canine chromosome 13 (rs9043975, p = 7.79x10 -16 ). Whole genome resequencing was used to identify causal variant(s) within a 414 kb critical interval. This approach highlighted an error in the CanFam3.1 dog assembly, which when resolved, led to the discovery of a c.2786G>A missense variant in exon 20 of the positional candidate gene, ADAM metallopeptidase with thrombospondin type 1 motif 3 ( ADAMTS3 ). In addition to segregating with UAS amongst Norwich Terriers, the ADAMTS3 c.2786G>A risk allele frequency was enriched among the BOAS-susceptible French and (English) Bulldogs. Previous studies indicate that ADAMTS3 loss of function results in lymphoedema. Our results suggest a new paradigm in the understanding of canine upper airway disease aetiology: airway oedema caused by disruption of ADAMTS3 predisposes dogs to respiratory obstruction. These findings will enhance breeding practices and could refine the prognostics of surgical interventions that are often used to treat airway obstruction.

Facial changes related to brachycephaly in Cavalier King Charles Spaniels with Chiari‐like malformation associated pain and secondary syringomyelia

“…Changes in the relative position and size of the soft palate and rostral skull flattening could be useful in providing further diagnostic indicators for CMSM. Although a thickened soft palate has been linked to brachycephaly and to otitis media with effusion in the CKCS, in this investigation, a thickened palate was not significant. Soft palate hypoplasia is a rare condition, and brachycephalic dogs typically have elongated soft palates with thickened superficial epithelium, extensive edema of the connective tissue, and mucous gland hyperplasia with several muscular alterations .…”

“…Soft palate hypoplasia is a rare condition, and brachycephalic dogs typically have elongated soft palates with thickened superficial epithelium, extensive edema of the connective tissue, and mucous gland hyperplasia with several muscular alterations . However, this is a secondary change to microtrauma or associated with genetic predisposition and it would appear from the results of the study that it is the proximity of the palate to the cranium that is significant with CM‐P and SM‐S, not the structure itself. This relative position for both hard and soft palate with respect to increased airorhynchy supports the view that CM‐P and SM‐S involve early embryological changes in the pervasive osseous reduction associated with para‐axial mesodermal insufficiency associated with CMSM and craniosynostosis that have already shown to exist with human CM/SM .…”

A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats

“…However, little is known about the genetic causes and interactions for brain malformation. Due to the health concerns associated with breed development, particularly in dog breeds [ 38 , 39 ], many breeders have become more vigilant to health-associated consequences of selection based on morphological phenotypes. Feline brain malformation syndrome seen in this extended family happened to be generated in the course of breeding selection for the ear morphological phenotype.…”

A deletion in GDF7 is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats

“…However, little is known about the genetic causes and interactions for brain malformation. Due to the health concerns associated with breed development, particularly in dog breeds [37,38], many breeders have become more vigilant to health-associated consequences of selection based on morphological phenotypes. In an effort to develop a breed of cats having similar phenotypes to a tiger, including a small rounded ear, a mixed breed cat derived from the Oriental cat breed was discovered to have small rounded ears, and hence, was used as a foundation sire for a breeding program.…”