Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 204650 (trait) , 104500 (trait) , 606585 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0008770: amelogenesis imperfecta type 1C

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific description: Also known as Enamel hypoplasia.

Mapping: After genotyping each of 22 affected and 49 normal Italian Grehounds with the Illumina CanineHD Genotyping BeadChip, which contains 173,662 SNPs, Gandolfi et al. (2013) conducted a GWAS which mapped the disorder to a 1.84 Mb region of chromosome CFA15, which contains 10 genes.

Molecular basis: Three of the ten genes in the candidate region described in the Mapping section above are involved in enamel development. Mutations in one of these three positional candidate genes (ENAM) are causal in one form of human amelogenesis imperfecta. Gandolfi et al. (2013) therefore chose to sequence the canine ENAM gene in three affecteds and one normal Italian Greyhound. Sequencing revealed the likely causal mutation as "a 5-bp deletion . . . , c.1991_1995delTTTCC, in exon 10, resulting in a frameshift and premature termination codon at position 668 (p.Phe665Argfs*3) of the protein". In Samoyed dogs, Pedersen et al. (2017) reported "Two potential deleterious mutations in SCL24A[4] on CFA8 and in strong linkage disequilibrium were ultimately identified in ARAI affected dogs, an asynonymous change (C to T) in exon 12 changing amino acid proline to leucine and a 21 bp duplication in exon 17". The extent to which either of these variants is actually associated with the disorder in this breed is not clear from the paper: the missense variant was not investigated beyond its discovery, and for the deletion variant, Pedersen et al. (2017) reported that "The 14/182 (7.8%) dogs that were presumed to have enamel hypoplasia based on physical examination and DNA testing all were homozygous for the mutation. Twenty of 168 (12%) heathy dogs were found to be heterologous [sic] for the mutation and most were parents or known close relatives of affected dogs." Thus it is not evident whether all dogs diagnosed solely on a clinical basis were homozygous and whether all known parents of affected dogs were heterozygous. Hytönen et al. (2019) reported a likely causal variant in Parson Russell Terriers: "A fully segregating missense variant (c.716C>T) in exon 8 of ENAM substitutes a well-conserved proline to leucine, p.(Pro239Leu), resulting in a clinical hypomineralization of teeth".

Clinical features: For Italian Greyhounds, the clinical signs as reported by Gandolfi et al. (2013) are "A brownish mottling and roughening of teeth is apparent in areas where enamel is thin or absent . . . . Affected permanent teeth are often small and pointed compared with normal teeth . . . . Greater than normal gaps between teeth are often noticeable in young dogs and become more apparent with age due to premature enamel wear".

Prevalence: Hytönen et al. (2019) reported a carrier frequency of 9% for the c.716C>T ENAM variant in Parson Russell Terriers.

Breeds: Greyhound (Dog) (VBO_0200638), Parson Russell Terrier (Dog) (VBO_0200987), Poodle, Standard (Dog) (VBO_0201056).
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: