Skip to main content

Research Repository

Advanced Search

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

Marchant, T W; Dietschi, E; Rytz, U; Schawalder, P; Jagannathan, V; Hadji Rasouliha, S; Gurtner, C; Waldvogel, A S; Harrington, R S; Drögemüller, M; Kidd, J; Ostrander, E A; Warr, A; Watson, M; Argyle, D; Ter Haar, G; Clements, D N; Leeb, T; Schoenebeck, J J


T W Marchant

E Dietschi

U Rytz

P Schawalder

V Jagannathan

S Hadji Rasouliha

C Gurtner

A S Waldvogel

R S Harrington

M Drögemüller

J Kidd

E A Ostrander

A Warr

M Watson

D Argyle

G Ter Haar

D N Clements

T Leeb

J J Schoenebeck


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.


Marchant, T. W., Dietschi, E., Rytz, U., Schawalder, P., Jagannathan, V., Hadji Rasouliha, S., …Schoenebeck, J. J. (in press). An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome. PLoS Genetics, 15(5), e1008102.

Journal Article Type Article
Acceptance Date Mar 19, 2019
Deposit Date May 18, 2019
Publicly Available Date May 20, 2019
Journal PLoS Genetics
Print ISSN 1553-7390
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 15
Issue 5
Pages e1008102
Public URL


Downloadable Citations