In other species: chimpanzee , domestic cat

Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 107970 (trait)

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Disease-related: yes

Key variant known: no

Species-specific name: Arrhythmogenic right ventricular cardiomyopathy

Species-specific symbol: ARVC

Species-specific description: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by monomorphic ventricular arrhythmias, syncope, and sudden cardiac death in Boxer dogs. Because the presenting sign can be sudden death, many dogs die without a diagnosis. Pathologic changes in the heart include dilation of the right ventricle and replacement of myocardial tissue with fibrous and fatty infiltrates. The mode of inheritance appears to be autosomal dominant with incomplete penetrance. A causative mutation has been identified in STRN. Edited by Meg Sleeper, VMD and Vicki N. Meyers-llen, VMD, PhD, Dipl. ACT Holdt et al. (2022) describe occurrence of arrhythmogenic right ventricular cardiomyopathy in Bulldogs. "Genetic testing of five cases revealed that the representative Bulldogs from this study did not have the striatin mutation that has been previously documented in Boxers."

Inheritance: Meurs et al. (2010) and Cattanach et al. (2015) reported autosomal dominance with mostly low penetrance, which means, in effect, that this disorder is multifactorial.

Mapping: By conducting a GWAS on 46 affected and 43 control Boxers, each genotyped with the Affymetrix Canine Genome 2.0 Array “Platinum Panel” (comprising 49,663 SNPs), Meurs et al. (2010) highlighted a region on chromosome CFA17. By fine-mapping and sequencing within the CFA17 candidate region, these authors identified an 8bp deletion in the 3’ UTR of STRN in strong (but not complete) association with ARVC in the Boxer: Chr17:29270913_29270920del (CanFam3.1). The variant overlaps with variant rs1152388415. Meurs et al. (2013) reported that the above STRN deletion is strongly associated with a closely related disorder, namely dilated cardiomyopathy (DCM) in Boxers. A pedigree analysis by Cattanach et al. (2015) confirmed the result of Meurs et al. (2010), namely that the STRN deletion is strongly but not completely associated with the disease. In other words, the STRN deletion is a marker for a QTL for liability to ARVC in Boxers. The variant has therefore been removed from OMIA's likely causal variant tables [26/01/2022]

Clinical features: Signs include monomorphic ventricular arrhythmias, syncope, and sudden cardiac death. Magnetic resonance imaging (MRI) demonstrates right ventricular dilation and aneurysms, reduced right ventricular ejection fraction, and bright anterolateral and/or infundibular ventricular signals corresponding with an infiltration of fatty tissue (Meurs et al, 2010). Dogs homozygous for the STRN mutation had, on average, more ventricular premature contractions (VPCs) than heterozygous dogs (Meurs et al., 2010). Although STRN is also highly expressed in neural tissue, affected dogs have no apparent neurologic deficits (Meurs et al., 2010).

Pathology: Frequent left bundle branch block morphology ventricular premature complexes cause the clinical signs (Meurs et al., 2010). The disorder causes a gradual and progressive right (and sometimes left) ventricular loss of muscle which is replaced with fat and fibrous tissue. Lesions include a thin right ventricular free wall, aneurysms, and myocyte loss starting at the epicardium (Basso et al., 2004).

Prevalence: Prevalence is thought to be very high in the USA, and it may also be prevalent in the Netherlands. True prevalence is unknown because many dogs likely die without a diagnosis.

Control: Breeding of affected dogs is not recommended.

Genetic testing: In assessing the results of Cattanach et al. (2015), Sargan (2015) discussed the pitfalls of basing a DNA test on "a mutation that has been thought to be the cause of a monogenic disease and has been treated as such in two commercial genetic testing laboratories [but which] is in fact not causal, but simply linked to the disease". DNA testing laboratories should heed this advice.

Breed: Boxer (Dog) (VBO_0200210).
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).