In other species: domestic cat , pig

Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 192600 (trait) , 271950 (trait) , 271960 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: no

Inheritance: From available pedigree evidence in the Newfoundland breed, Pyle et al (1976) concluded that this disorder is polygenic. From a pedigree analysis of "more than 230,000 Newfoundland dogs from the European and North American population reaching back to the 19th century including 6023 dogs with a SAS diagnosis", Reist-Marti et al. (2014) concluded that "The only simple mode of inheritance that fitted the data well was autosomal codominant with lethal homozygosity and a penetrance of 1/3 in the heterozygotes", which, in effect, is polygenic inheritance. Ohad et al. (2013) provided evidence for autosomal recessive inheritance in Dogue de Bordeaux dogs in Israel. From a pedigree of 45 Newfoundlands, Stern et al. (2014) concluded, in essence, polygenic inheritance.

Mapping: By conducting a genome-wide association study (GWAS) on 38 Newfoundland dogs, unrelated for three generations, comprising 20 controls and 18 affecteds, each genotyped with the CanineHD BeadChip (yielding 122,184 informative SNPs), Stern et al. (2014) identified 13 candidate regions, each on a different chromosome; a result consistent with polygenic inheritance.

Molecular basis: The GWAS results of Stern et al. (2014) were not sufficient to enable them to identify a primary candidate region. Consequently, they compared sequenced DNA copies of RNA from "regions of subvalvular aortic stenosis and ridge tissue" from two affected and six non-affected Newfoundland dogs. Among the sequences that mapped to the thirteen candidate regions from the GWAS, Stern et al. (2014) identified "a three-nucleotide exonic insertion in phosphatidylinositol-binding clathrin assembly protein (PICALM)" (K599_L600insL) as the most likely causal mutation. An association analysis of this mutation in "26 affected Newfoundland dogs, 23 non-affected Newfoundland dogs and 180 control dogs of 30 different breeds" revealed this mutation to be associated but not in itself causal: "25 of 26 SAS-affected Newfoundland dogs possessed the insertion mutation (9 homozygous, 16 heterozygous); 6 of 23 non-affected Newfoundland dogs possessed the mutation (1 homozygous, 5 heterozygous); and none of 180 control dogs of 30 breeds possessed the mutation in any form". Drögemüller et al. (2015) genotyped this mutation in 399 Newfoundland dogs, including 88 affecteds, 8 equivocals, and 6 affected (all classified according to the same criteria as used by Stern et al., 2014), plus 300 non-affected dogs from 64 breeds. They concluded that "the PICALM:p.K599_L600insL variant is not causally involved in the development of SAS in Newfoundland dogs, but rather a neutral variant that occurs at high frequencies in Newfoundland dogs and is rare or absent in most other dog breeds. Consequently, the genotype at this variant is not a meaningful predictor of SAS risk."

Breed: Newfoundland (Dog) (VBO_0200938).
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).