Immunodeficiency, CARD9-related

Gene: CARD9

Transmission: Autosomal, recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Deletion, CARD9 gene; c.493_495, p.(Lys165del), exon3, chromosome 9.

Breed: Miniature Schnauzer

Medical system: Immunological

Age of onset of symptoms: 1.5 to 8 years, average age of 2.5 years.

Primary immunodeficiency disorders are caused by genetic mutations that confer a predisposition of an animal to specific infections, including yeast, fungal or mycobacterial infections.   The Miniature Schnauzer breed is known to have a susceptibility to mycobacterium infections.  Animals suffering from mycobacterium infections show signs including anorexia, lethargy, diarrhea, fever, lameness lymphadenopathy, lymphadenopathy and hepatosplenomegaly.  Clinical signs are progressive, and death, often by euthanasia, usually within one year of diagnosis.  Mycobacterium avium infection of tissues can be confirmed by bacterial culture.

DNA studies were performed to explore the genetics of the susceptibility of Miniature Schnauzers to mycobacterium infections, using 8 related infected animals and 9 non infected relatives as well as 160 non infected control animals.   A mutation within the CARD9 gene was identified that was homozygote in infected animals and heterozygote in obligate carrier animals, indicating autosomal recessive heredity.  The CARD9 gene codes for a signaling pathway protein involved in mediating the inflammatory response to infectious agents.  In humans, mutations in the CARD9 gene are associated with familial susceptibilities to yeast and mycobacterial infections.

Pedigree analysis of infected Miniature Schnauzers identified a common ancestor born in 1986 that had been a popular international sire.  Further frequency testing of 7091 international Miniature Schnauzers revealed a carrier rate for the CARD9 mutation of 4.78%.  Veterinarians and breeders of Miniature Schnauzers should be aware of the CARD9 immunodeficiency disorder in this breed. DNA testing should be performed for animals displaying clinical signs as well as animals that are to be used for reproduction, in order to control and eventually eliminate this disease from the Miniature Schnauzer breed.

Note that Mycobacterium avium can cause zoonotic infections in immunosuppressed individuals as well as in the very young and old. 

References:

OMIA link: [2854-9615]

Mizukami K, Dorsey-Oresto A, Raj K, et al. (2024) Increased susceptibility to Mycobacterium avium complex infection in miniature Schnauzer dogs caused by a codon deletion in CARD9. Sci Rep 14:10346.  [pm/38710903]

Ghielmetti G, Giger, U. (2020). Mycobacterium avium: an Emerging Pathogen for Dog Breeds with Hereditary Immunodeficiencies. Current clinical microbiology reports, 7(3), 67–80.  [pm/33842195]

Contributed by: Angelina Pistilli and Kiara Tommasini, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal.  (Translation DWS)