Categories: Digestive / alimentary phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 261800 (trait) , 600030 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: Palatoschisis

Species-specific symbol: CP1

Species-specific description: See 'OMIA:001140-9615 : Cleft lip with or without cleft palate, ADAMTS20-related' for a different form of clef palate in Nova Scotia Duck Tolling retrievers.

Mapping: From a GWAS conducted on 14 affected and 72 normal Nova Scotia Duck Tolling Retrievers, each genotyped with the Illumina CanineHD BeadChip (yielding 109,506 informative SNPs), Wolf et al. (2014) mapped this disorder in this breed to a 5.1Mb region (24.2 Mb to 29.3 Mb; CanFam2.0) on chromosome CFA14.

Molecular basis: Among the 21 positional candidate genes in the region to which this disorder was mapped (see Mapping section), Wolf et al. (2014) identified two (DLX5 and DLX6) as functional candidates (being transcription factors involved in craniofacial development; and containing causal mutations in mice). Sanger sequencing of the coding regions and conserved introns of these two genes in 1 affected and 1 unaffected Nova Scotia Duck Tolling Retriever revealed a "2056 bp [LINE-1] insertion . . . within a highly conserved region of DLX6 intron 2 at cfa14.25016716" as the most likely causal mutation. As reported by the same authors, "The LINE-1 insertion is predicted to insert a premature stop codon within the homeodomain of DLX6." Genotyping for this mutation in a range of families in which the disorder is segregating confirmed it as causal.

Clinical features: As reported by Wolf et al. (2014), this syndrome is best summarised as "relative mandibular brachygnathia and cleft palate". As detailed by the same authors, in the syndrome specified as CP1 "clefts were characterized by abnormal or missing palatine fissures, missing or small palatine processes of the maxilla, and small, missing, or abnormally shaped palatine bones . . . The nasal septum was absent or poorly developed. . . .variation from the normal angulation of the condylar process [of mandibles] was observed". These same authors also reported that "CP1 NSDTRs [Nova Scotia Duck Tolling Retrievers] had relatively shorter mandibles by an average of 5.46 mm when compared to the normal NSDTRs".

Prevalence: As reported by Wolf et al. (2014), "Within the NSDTR breed, 96 dogs were genotyped and 80 NSDTRs did not carry the insertion, while the remaining 16 NSDTRs were heterozygous for the insertion. To determine if the insertion was shared among other breeds, 35 affected dogs from 20 other breeds and 284 unaffected dogs from 69 breeds were genotyped. No carriers were identified. This is consistent with a fully penetrant autosomal recessive causative mutation that is private to the NSDTR breed."

Breed: Nova Scotia Duck Tolling Retriever (Dog) (VBO_0200964).
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: