OMIA 000952-9615 : Subaortic stenosis in Canis lupus familiaris

In other species: domestic cat , pig

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 192600 , 271950 , 271960

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: 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.

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2015 Drögemüller, M., Jagannathan, V., Dolf, G., Butenhoff, K., Kottmann-Berger, S., Wess, G., Leeb, T. :
A single codon insertion in the PICALM gene is not associated with subvalvular aortic stenosis in Newfoundland dogs. Hum Genet 134:127-9, 2015. Pubmed reference: 25391634. DOI: 10.1007/s00439-014-1506-5.
Kander, M., Pasławska, U., Staszczyk, M., Cepiel, A., Pasławski, R., Mazur, G., Noszczyk-Nowak, A. :
Retrospective analysis of co-occurrence of congenital aortic stenosis and pulmonary artery stenosis in dogs. Pol J Vet Sci 18:841-5, 2015. Pubmed reference: 26812828. DOI: 10.1515/pjvs-2015-0109.
2014 Eason, B.D., Fine, D.M., Leeder, D., Stauthammer, C., Lamb, K., Tobias, A.H. :
Influence of Beta Blockers on Survival in Dogs with Severe Subaortic Stenosis. J Vet Intern Med :, 2014. Pubmed reference: 24597738. DOI: 10.1111/jvim.12339.
Stern, J.A., White, S.N., Lehmkuhl, L.B., Reina-Doreste, Y., Ferguson, J.L., Nascone-Yoder, N.M., Meurs, K.M. :
A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. Hum Genet 133:1139-48, 2014. Pubmed reference: 24898977. DOI: 10.1007/s00439-014-1454-0.
2013 Ohad, D.G., Avrahami, A., Waner, T., David, L. :
The occurrence and suspected mode of inheritance of congenital subaortic stenosis and tricuspid valve dysplasia in Dogue de Bordeaux dogs. Vet J 197:351-7, 2013. Pubmed reference: 23434219. DOI: 10.1016/j.tvjl.2013.01.012.
2012 Reist-Marti, S.B., Dolf, G., Leeb, T., Kottmann, S., Kietzmann, S., Butenhoff, K., Rieder, S. :
Genetic evidence of subaortic stenosis in the Newfoundland dog. Vet Rec 170:597, 2012. Pubmed reference: 22645160. DOI: 10.1136/vr.100019.
2011 Oliveira, P., Domenech, O., Silva, J., Vannini, S., Bussadori, R., Bussadori, C. :
Retrospective Review of Congenital Heart Disease in 976 Dogs. J Vet Intern Med :, 2011. Pubmed reference: 21418326. DOI: 10.1111/j.1939-1676.2011.0711.x.
2010 Quintavalla, C., Guazzetti, S., Mavropoulou, A., Bussadori, C. :
Aorto-septal angle in Boxer dogs with subaortic stenosis: An echocardiographic study. Vet J 185:332-337, 2010. Pubmed reference: 19665399. DOI: 10.1016/j.tvjl.2009.06.027.
2009 Jenni, S., Gardelle, O., Zini, E., Glaus, TM. :
Use of auscultation and Doppler echocardiography in Boxer puppies to predict development of subaortic or pulmonary stenosis. J Vet Intern Med 23:81-6, 2009. Pubmed reference: 19175725. DOI: 10.1111/j.1939-1676.2008.0213.x.
2006 Chetboul, V., Trollé, J.M., Nicolle, A., Carlos Sampedrano, C., Gouni, V., Laforge, H., Benalloul, T., Tissier, R., Pouchelon, J.L. :
Congenital heart diseases in the boxer dog: A retrospective study of 105 cases (1998-2005). J Vet Med A Physiol Pathol Clin Med 53:346-51, 2006. Pubmed reference: 16922831. DOI: 10.1111/j.1439-0442.2006.00865.x.
2005 Freedom, RM., Yoo, SJ., Russell, J., Perrin, D., Williams, WG. :
Thoughts about fixed subaortic stenosis in man and dog. Cardiol Young 15:186-205, 2005. Pubmed reference: 15845164. DOI: 10.1017/S1047951105000399.
2003 Baumgartner, C., Glaus, TM. :
[Congenital cardiac diseases in dogs: a retrospective analysis]. Schweiz Arch Tierheilkd 145:527-33, 535-6, 2003. Pubmed reference: 14639823.
2000 Orton, E.C., Herndon, G.D., Boon, J.A., Gaynor, J.S., Hackett, T.B., Monnet, E. :
Influence of open surgical correction on intermediate-term outcome in dogs with subvalvular aortic stenosis: 44 cases (1991-1998) Journal of the American Veterinary Medical Association 216:364-367, 2000. Pubmed reference: 10668534.
Pyle, R.L. :
Interpreting low-intensity cardiac murmurs in dogs predisposed to subaortic stenosis Journal of the American Animal Hospital Association 36:379-382, 2000. Pubmed reference: 10997510.
1998 Demoraes, A.N., Dyson, D.H., Ogrady, M.R., Mcdonell, W.N., Holmberg, D.L. :
Plasma concentrations and cardiovascular influence of lidocaine infusions during isoflurane anesthesia in healthy dogs and dogs with subaortic stenosis Veterinary Surgery 27:486-497, 1998. Pubmed reference: 9749521.
1996 Monnet, E., Orton, E.C., Gaynor, J.S., Boon, J., Wagner, A., Linn, K., Eddleman, L.A., Brevard, S. :
Open resection for subvalvular aortic stenosis in dogs Journal of the American Veterinary Medical Association 209:1255-1261, 1996. Pubmed reference: 8837645.
Nakayama, T., Wakao, Y., Ishikawa, R., Takahashi, M. :
Progression of subaortic stenosis detected by continuous wave doppler echocardiography in a dog Journal of Veterinary Internal Medicine 10:97-98, 1996. Pubmed reference: 8683489.
Swift, S. :
The problem of inherited diseases. 2. Subaortic stenosis in Boxers Journal of Small Animal Practice 37:351-352, 1996. Pubmed reference: 8840258.
1994 Kienle, R.D., Thomas, W.P., Pion, P.D. :
The natural clinical history of canine congenital subaortic stenosis Journal of Veterinary Internal Medicine 8:423-431, 1994. Pubmed reference: 7884729.
Lehmkuhl, L.B., Bonagura, J.D. :
Comparison of Transducer Placement Sites for Doppler Echocardiography in Dogs with Subaortic Stenosis American Journal of Veterinary Research 55:192-198, 1994. Pubmed reference: 8172406.
1993 Delellis, L.A., Thomas, W.P., Pion, P.D. :
Balloon Dilation of Congenital Subaortic Stenosis in the Dog Journal of Veterinary Internal Medicine 7:153-162, 1993. Pubmed reference: 8331609.
1978 Muna, WF., Ferrans, VJ., Pierce, JE., Roberts, WC. :
Discrete subaortic stenosis in Newfoundland dogs: association of infective endocarditis. Am J Cardiol 41:746-54, 1978. Pubmed reference: 565582.
1976 Critchley, KL. :
Sub-aortic stenosis in a Boxer dog. J Small Anim Pract 17:319-21, 1976. Pubmed reference: 945430.
Pyle, RL., Patterson, DF., Chacko, S. :
The genetics and pathology of discrete subaortic stenosis in the Newfoundland dog. Am Heart J 92:324-34, 1976. Pubmed reference: 986114.
1967 Flickinger, G.L., Patterson, D.F. :
Coronary lesions associated with congenital subaortic stenosis in the dog Journal of Pathology and Bacteriology 93:133-140, 1967. Pubmed reference: 6067618. DOI: 10.1002/path.1700930113.
1963 Patterson, D.F., Detweiler, D.K. :
Predominance of German Shepherd and Boxer breeds among dogs with congenital subaortic stenosis American Heart Journal 65:249-430, 1963. Pubmed reference: 13941902.

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  • Created by Frank Nicholas on 06 Sep 2005
  • Changed by Frank Nicholas on 08 Jun 2012
  • Changed by Frank Nicholas on 22 May 2013
  • Changed by Frank Nicholas on 08 Mar 2015