In other species: turkey , domestic cat , pig , taurine cattle , rabbit , golden hamster , sea otter , meerkat , black-pencilled marmoset

Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 107970 (trait) , 115200 (trait) , 611880 (trait) , 302060 (trait) , 302045 (trait) , 600884 (trait) , 601494 (trait)

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Disease-related: yes

Key variant known: no

Key variant is published: no

Cross-species summary: A disorder characterised by cardiac enlargement (especially of the left ventricle), poor myocardial contractility, and congestive heart failure. This disorder occurs in many different forms (see gene specific entries), some of which are not inherited.

Species-specific name: Dilated cardiomyopathy

Species-specific symbol: DCM

Species-specific description: See also gene specific entries for dilated cardiomyopathy such as: 'OMIA:002365-9615 Cardiomyopathy, dilated, RBM20-related', OMIA:002195-9615 Cardiomyopathy, dilated, PLN-related', OMIA:002796-9615 : Cardiomyopathy, dilated, LMNA-related, and OMIA:002710-9615 : Cardiomyopathy, dilated, ABCC9-related

Inheritance: A juvenile form of this disorder, unique to Portugese water dogs, is autosomal recessive (Dambach et al., 1999; Alroy et al., 2000; Sleeper et al., 2002). In Doberman pinschers, Meurs et al. (2007) reported autosomal recessive inheritance with incomplete penetrance, which is, in effect, multifactorial inheritance. Oertle et al. (2023) report a recessive form of the disease in Nova Scotia Duck Tolling Retrievers.

Mapping: A genome scan by Werner et al. (2008) of 40 affected and 69 normal Portuguese water dogs, each genotyped with an initial set of 120 microsatellites, mapped this disorder in this breed to a 3.9Mb region of chromosome CFA8. As part of the LUPA consortium, Mausberg et al. (2011) conducted a GWAS on 71 affected and 70 control Doberman Pinschers, each of which was genotyped with the Illumina Canine HD chip (yielding 75,916 informative SNPs for analysis). The results indicated that a risk factor located in a 3 Mb region between 52 Mb and 55 Mb on chromosome CFA5 is responsible for about 50% of the dilated cardiomyopathy cases in Doberman Pinschers from Europe. Philipp et al (2012) conducted GWAS in 190 Irish Wolfhounds and identified six distinct loci, but no causal variant was identified. A GWAS conducted by Meurs et al. (2012) on 48 affected and 48 control Doberman pinschers, each genotyped with the Affymetrix Canine Genome 2.0 Array “Platinum Panel” (comprising 49,663 SNPs), highlighted a region on chromosome CFA14. Subsequent fine mapping reduced the region to 23,774,190–23,781,919. A GWAS conducted by Philipp et al. (2012) on 106 affected and 84 control Irish Wolfhounds, each genotyped with the Illumina HD beadchip (yielding 83,621 SNPs for analysis), highlighted a region on chromosome CFA37, and less-significant regions on CFA1, 10, 15, 17, and 21. Niskanen et al. (2023) investigated dilated cardiomyopathy (DCM) in a large study including 540 affected and healthy Dobermanns from Europe. The authors “performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses … . Canine gene discovery was followed up in three human DCM cohorts. … [The study] revealed two independent additive loci [on chromosome 5] associated with the typical DCM phenotype ... . ... [The authors] assessed the role of previously indicated Dobermann and human DCM loci and genes in [their] GWAS cohort. Other than the redefinition of the chr5:50–51 Mb locus described above [Mausberg et al., 2011], [the authors] did not detect any signal at the previously claimed Dobermann DCM loci at chr14:20.9 Mb (PDK4, known as “DCM1” gene test) [Meurs et al., 2012] and chr36:22.3 Mb (TTN, known as “DCM2” gene test) [Meurs et al., 2019] or regions corresponding to human DCM loci … . [The authors] highlight two novel candidate genes, RNF207 and PRKAA2, … . RNA analyses highlight alternatively spliced transcripts in RNF207 and PRKAA2 and suggest that aberrant RNA processing may be involved in the molecular mechanisms of DCM in Dobermanns. While the RNF207 splice site variant [chr5:60,111,983G > A, c.1297-1G > A] was demonstrated to result in an altered transcript, no clear candidate variants explaining the aberrant splicing of PRKAA2 were found." Polenberg et al. (2024) "conducted a genome-wide association study (GWAS) leveraging a database of genetic profiles obtained through collaboration with the Doberman Diversity Project (DDP). ...  our study included data on 216,184 single nucleotide polymorphisms (SNPs) in 46 cases and 3226 population control Doberman Pinschers. Using a generalized linear mixed model and saddlepoint approximation to correct for unbalanced group sizes, we identified a cluster of SNPs associated with DCM on chromosome 16."

Markers: Sequencing within their CFA14 candidate region (see Mapping section) enabled Meurs et al. (2012) to report "a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 [PDK4] gene" associated with the disorder in Dobermans. Their data showed that the deletion occurred in 82% of affected dogs and 39% of unaffected dogs, indicating that it is far from being causative. It could, however, be linked to a QTL for liability for the disorder. This PDK4 variant is not specific to Doberman Pinschers and it was not associated with DCM in the Doberman cohort from the European LUPA project (Owczarek-Lipska et al. 2013). Furthermore, the study by Niskanen et al. (2023) did not detect an association between PDK4 and dilated cardiomyopathy in European Doberman Pinschers. Meurs et al. (2013) reported that the 8bp deletion in the striatin (STRN) gene that is responsible for Arrhythmogenic right ventricular cardiomyopathy (OMIA:000878-9615) in Boxers, is strongly (but not completely) associated with dilated cardiomyopathy in Boxers. Meurs et al. (2019) reported a GWAS that highlighted a variant in the TTN (titin) gene, noting that "in the overall population of Doberman Pinschers evaluated, many dogs had the variant but have not developed the disease." Niskanen et al. (2023) did not detect such an association between TTN in their Doberman study. Oertle et al. (2023) report in proceedings of the UC Davis Student Training Symposium a laminin-A (LMNA) variant which "results in severe juvenile DCM [dilated cardiomyopathy], variable cardiac arrhythmias, fulminant myocardial fibrosis, and most commonly SCD [sudden cardiac death]." See OMIA:002796-9615 : Cardiomyopathy, dilated, LMNA-related in Canis lupus familiaris for additional details.

Clinical features: Clinical features of canine dilated cardiomyopathy (DCM) can have a sudden onset and often present secondary to diminished cardiac pumping function. This can manifest as decreased oxygenated blood delivery to the body (lethargy, weakness, exercise intolerance, collapse) or pulmonary blood congestion (coughing, tachypnoea, dyspnoea) (Tidholm and Jönsson, 1996). Radiographic evidence of ascites or pleural effusion, and pulmonary oedema, are also clinical features of DCM (Harmon et al., 2017). Echocardiography may reveal a systolic murmur and hypokinesis (Tidholm et al., 2001). [IT thanks DVM student Lexie Hunter, who provided the basis of this contribution in April 2022.]

Pathology: Gross post-mortem pathological findings of canine DCM indicate eccentric left ventricular hypertrophy (Tidholm and Jönsson, 2005; Harmon et al., 2017) and secondary left atrial dilation (Dukes-McEwan et al., 2003; Tildholm et al., 2001[Veterinary Journal]). Myocardial changes seen histologically include increased interstitial collagen deposition and macrophage infiltration, in addition to reduced contractile tissue and cardiomyocyte degeneration (Gasparini et al., 2020). [IT thanks DVM student Lexie Hunter, who provided the basis of this contribution in April 2022.]

Genetic testing: A DNA test for a linked marker of a juvenile form of this disorder (JDCM) in Portugese Water Dogs is included in the OFA's list at http://www.offa.org/dna_alltest.html, which directs enquiries to the PennGen laboratories, Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania: http://research.vet.upenn.edu/penngen. This linked marker is presumably based on the CFA8 results of Werner et al. (2008). A DNA test for this disorder in Dobermans was included in the OFA's list in the past. The basis for this test was the linked marker reported by Meurs et al. (2012). Given the results of Meurs et al. (2012), Owczarek-Lipska et al. (2013) and Niskanen et al. (2023), it is evident that any DNA test based on this mutation will not be a good indicator of liability to this disorder in Dobermans. See gene specific entries mentioned in the 'Species-specific description' of this entry for additional information.

Breeds: Borzoi (Dog) (VBO_0200197), Boxer (Dog) (VBO_0200210), Cocker Spaniel (Dog) (VBO_0200372), Doberman Pinscher (Dog) (VBO_0200442), English Cocker Spaniel (Dog) (VBO_0200486), Great Dane (Dog) (VBO_0200623), Irish Wolfhound (Dog) (VBO_0200706), Newfoundland (Dog) (VBO_0200938), Nova Scotia Duck Tolling Retriever (Dog) (VBO_0200964), Portuguese Water Dog (Dog) (VBO_0201077), Weimaraner (Dog) (VBO_0201401).
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).