Categories: Respiratory system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 605011 (gene)

Mendelian trait/disorder: unknown

Disease-related: yes

Year key variant first reported: 2019

Species-specific name: upper airway obstructive syndrome; upper respiratory tract (URT) disorder

Species-specific symbol: UAS

Species-specific description: For upper airway obstructive syndrome in brachycephalic dog breeds see also: OMIA:000145-9615 : Brachycephalic obstructive airway syndrome in Canis lupus familiaris

Mapping: By conducting a GWAS on 401 Norwich Terrier dogs, each genotyped with the CanineHD bead chip (yielding 105,130 informative SNPs), Marchant et al. (2019) mapped this disorder to a ~2.9Mb region "58,941,974–61,830,084 bp on canine chromosome (CFA) 13". Subsequent fine-mapping revealed a "413 kb haplotype spanning chr13:61,166,179–61,579,985 that is shared among most severely affected Norwich Terriers".

Molecular basis: Whole-genome sequencing within the fine-mapped region (see Mapping section) led Marchant et al. (2019) "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)" as a likely causal variant.

Clinical features: Norwich terriers with upper airway obstructive syndrome have normal nasal passages and nostrils. Affected dogs main anatomical abnormalities consisted of mildly elongated soft palates, additional dorsal pharyngeal tissue with elimination of piriform recesses, abnormal laryngeal mucosa, abnormal cuneiform and or corniculate processes, partially or full everted ventricles (saccules) and abnormal keyhole shape to the lower larynx. These changes manifest as respiratory signs of varying severities. Mildly affected dogs have owner reports of intermitted stridor (snoring) or stertor (wheezing). Dogs which are severely affected have been reported to experience severe respiratory distress, collapse and asphyxiation. (Johnson et al., 2013; Marchant et al., 2019) IT thanks DVM student Amy Garber, who provided the basis of this contribution in May 2023.

Prevalence: Marchant et al. (2019): "Over 1,300 dogs representing up to 114 diverse breeds including representatives of brachycephalic breeds diagnosed with BOAS [Brachycephalic Obstructive Airway Syndrome] were screened for the c.2789G>A variant . . . . The disease allele frequency (AF) was observed in the Norwich Terrier (AF = 0.57, n = 401), Bulldog (AF = 0.85, n = 41), French Bulldog (AF = 0.12, n = 23), Staffordshire Bull Terrier (AF = 0.125, n = 8), German Spitz (Mittel) (AF = 0.06, n = 8) and Pomeranian (AF = 0.06, n = 8) suggesting the variant may influence BOAS in the French and English Bulldogs."

Breed: Norwich Terrier (Dog) (VBO_0200962).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: