Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 611927 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific name: Dry eye curly coat syndrome

Species-specific symbol: CKCSID

Mapping: By conducting a GWAS on 23 affected and 38 control Cavalier King Charles Spaniels, each genotyped with the Illumina Canine HD SNP chip (yielding 91,427 SNPs for analysis), Forman et al. (2012) highlighted a region on chromosome CFA13.

Molecular basis: By sequencing their candidate region (see Mapping section) in affected and normal dogs, Forman et al. (2012) eventually revealed the causative mutation as a "single base deletion in exon 5" in a gene with the somewhat unusual name of Family with sequence similarity 83, member H (FAM83H). Using the genetic variant nomenclature as of 2015, the cuastaive variant can be descripted as c.977delC or p.Pro326Hisfs*258.

Clinical features: CKCSID presents as a combination of two primary disease processes: Keratoconjunctivitis sicca: Decreased tear production leads to drying of the surface of the eye. Common signs include redness in one or both eyes, with a thick mucoid discharge. Chronic dry eyeball surfaces often predisposes to corneal ulceration and further painful secondary bacterial conjunctivitis (Barnett, 2006). Ichythyosiform dermatosis: Typically presents as a rough and curly coat with possible multifocal alopecia. The epidermis is generally dry, scale-like, and flakes off, particularly around the dorsal spine and lateral flankregion. The abdominal venter may be hyperpigmented, whilst the footpads typically show signs of hyperkeratinization. The nails may present with marked growth abnormalities (Hartley et al., 2012). [IT thanks DVM student Tom Spunar, who provided the basis of this contribution in April 2022]

Pathology: Keratoconjunctivitis sicca develops as a result of decreased aqueous tear production and mucin secretion, leading to progressive loss of the precorneal tear film (PTF) This predisposes it to damage and infection. The exact pathway is poorly understood, but is thought to be due to a neurofunctional abnormality in the lacrimal glands of affected dogs. Dryness and the loss of the tear film leads to profound irritation, diffuse hyperaemia and predisposes secondary conjunctivitis (Hartley et al., 2012). Ichythyosiform dermatosis is characterized as a cutaneous scaling and hyperkeratinization disorder. It develops due to an abnormal rate of cell turnover in outer layer of epidermis, the stratum corneum. Hyperplastic dysregulation of these cells culminates in a loss of the epithelial ‘brick and mortar’ structure. This increased cellular turnover leads to progressive drying and flaking of exterior layers which is exacerbated by increased lipid deposition and further inflammatory mediators (Mauldin, 2013). [IT thanks DVM student Tom Spunar, who provided the basis of this contribution in April 2022]

Breed: Cavalier King Charles Spaniel (Dog) (VBO_0200309).
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: