Test Detail

Multi-disease genetic panel for the Kromfohrländer grouping six molecular tests: von Willebrand disease type 1 (vWD1), hereditary digital hyperkeratosis (HFH, FAM83G), hyperuricosuria (HUU, SLC2A9), degenerative myelopathy (DM, exon 2 variant of SOD1), ABCB1/MDR1 gene variant (drug sensitivity) and furnishing (hard coat/eyebrows, RSPO2). It combines clinical conditions with a pharmacogenetic marker and a coat trait. The panel is complementary to, not a substitute for, clinical examination and breeding follow-up.

Applicable breed: Kromfohrländer. The FAM83G c.155G>C variant is described in the Kromfohrländer and Irish Terrier (and Bedlington Terrier); the population series of the Dogue de Bordeaux (KRT16, different molecular basis) showed ~20 % carriers, but this is not extrapolable to the Kromfohrländer. HUU, DM, the MDR1 defect and furnishing are pan-breed tests without published evidence specific to the Kromfohrländer (limited data). vWD1 and HFH (FAM83G) are documented in the breed. There are no reliable carrier frequencies in the Kromfohrländer breeding population.

- Prolonged bleeding after surgery or trauma, epistaxis, haematuria and gingival bleeding (vWD1)
- Hyperkeratosis of the paw pads with painful fissures, lameness and secondary infection (HFH)
- Urate urolithiasis with dysuria, haematuria and urethral obstruction (HUU)
- Progressive paresis and ataxia of the hind limbs with proprioceptive loss (DM)
- Neurotoxicity from ivermectin, moxidectin, loperamide and other P-glycoprotein substrates (MDR1)
- Hard coat, eyebrows and beard (furnishing): coat trait, not a disease

Canine vWD1 was first described in the Doberman Pinscher (VWF c.7437G>A variant; Brooks 2001; Crespi 2018). In the Kromfohrländer the same VWF c.7437G>A variant has been documented with autosomal dominant inheritance of incomplete penetrance (Segert 2019). HFH was associated with FAM83G c.155G>C in the Kromfohrländer and Irish Terrier (Drögemüller 2014). HUU was linked to SLC2A9 (Bannasch 2008). Canine DM was associated with the exon 2 variant of SOD1 (Awano 2009). Ivermectin sensitivity was associated with a 4 bp deletion in ABCB1/MDR1 (Mealey 2001). Furnishing was associated with a 167 bp insertion in RSPO2 (Cadieu 2009; Parker 2010).

- Genotype breeding animals with the panel before mating, using the test for the variant corresponding to the breed
- vWD1: autosomal dominant with incomplete penetrance (documented in the breed, Segert 2019); consider mating with a clear animal and complement with determination of the vWF level
- HFH, HUU and DM (recessive): do not mate two carriers (25 % affected homozygotes); carrier x clear is admissible if the offspring intended for breeding is tested
- MDR1 (dose effect): do not mate two carriers; inform the buyer and the veterinarian to avoid ivermectin, moxidectin, loperamide and other P-gp substrates in homozygotes and heterozygotes
- Furnishing: use the test as coat selection, not as disease screening, and interpret it together with other coat loci
- After a confirmed clinical case, do not repeat the parental mating

vWD1 is confirmed by assay of von Willebrand factor antigen and activity; assess before scheduled surgery. HFH is confirmed by clinical signs and molecular test (or biopsy); the differential includes nasal parakeratosis of the Labrador (SUV39H2), epidermolytic ichthyosis of the Norfolk Terrier, leishmaniosis, pemphigus and zinc deficiency. Urate urolithiasis must be differentiated from cystine and infectious urolithiasis (stone analysis). DM is a diagnosis of exclusion (rule out spinal cord compression). Do not apply affected/carrier medical language to furnishing.

1. vWD1 (VWF): Segert JH et al. 2019. vWD1 is inherited in an autosomal dominant manner with incomplete penetrance, in the Kromfohrländer breed. Canine Genet Epidemiol. PMID: 31131110; Brooks M et al. 2001. von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers. Am J Vet Res. PMID: 11277201; Crespi JA et al. 2018. von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence. J Vet Diagn Invest. PMID: 29271313; OMIA:001057-9615
2. HFH (FAM83G): Drögemüller M et al. 2014. A mutation in the FAM83G gene in dogs with hereditary footpad hyperkeratosis. PLoS Genet. PMID: 24832243; OMIA:001327-9615 (KRT16/FNEPPK1 del Dogo de Burdeos: Plassais J et al. 2015. J Invest Dermatol. PMID: 25521457; OMIA:002088-9615)
3. HUU (SLC2A9): Bannasch D et al. 2008. Mutations in the SLC2A9 gene cause hyperuricosuria and hyperuricemia in the dog. PLoS Genet. PMID: 18989453; Karmi N et al. 2010. Validation of a urine test. Am J Vet Res. PMID: 20673090; OMIA:001033-9615
4. DM (SOD1): Awano T et al. 2009. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy. Proc Natl Acad Sci U S A. PMID: 19188595; Coates JR et al. 2010. Canine degenerative myelopathy. Vet Clin North Am Small Anim Pract. PMID: 20732599; OMIA:000263-9615
5. MDR1 (ABCB1): Mealey KL et al. 2001. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. PMID: 11692082; Mealey KL. 2004. Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Ther. PMID: 15500562
6. Furnishing (RSPO2): Cadieu E et al. 2009. Coat variation in the domestic dog is governed by variants in three genes. Science. PMID: 19713490; Parker HG et al. 2010. An insertion in the RSPO2 gene correlates with improper coat in the Portuguese water dog. J Hered. PMID: 20562213