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Therefore, as with any genetic information, we recommend ALWAYS using test results to guide your decisions about breeding rather than using them as an absolute recommendation for all dogs. Do not make drastic decisions. Each dog and each family line should be considered individually. The field of canine genetics is very new and the field of cardiac genetics is very complex. We are still learning how to best use these tools.
~Dr. Kathryn Meurs, February 2010 Update to the American Boxer Charitable Foundation

After nearly a decade of research, Dr. Kathryn Meurs of Washington State University announced in April 2009 that she, in collaboration with the Broad Institute, had discovered a gene mutation that is correlated with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in Boxers. ARVC causes ventricular premature contractions (VPCs) which can lead to exercise intolerance, fainting (syncope) and, in severe cases, sudden death.

The significance of this mutation is still being explored and debated. The original hope that this gene was the gene quickly faded, as test results failed to correspond with expectations (dogs with multiple clear holters, and multiple generations of holtered dogs behind them, tested as homozygous positive; clearly affected dogs tested as negative for the mutation). This problem was especially noticeable in the UK Boxer population, where they have a good handle on where the cardiomyopathy problem is in their breed and yet the results still did not meet expectations. UK geneticist and Boxer breeder Dr. Bruce Cattanach, in consultation with breeders and cardiologists in that country, has stated that the gene test "does not seem to have any relevance for UK Boxers". Dr. Kerstin Lindblad-Toh of the Broad Institute noted that, in her opinion, the discovered gene "is one of two or three genes together causing the disease". In Dr. Meurs' update to the American Boxer Charitable Foundation, she admitted that "it is very likely that there is more than one mutation in the Boxer dog that may lead to the disease in some lines of dogs", that "some individuals with the mutation will NEVER show the disease", and that "multiple genes could work together to impact the severity of the disease in the dog." Clearly, there is still much research to be done, and while this gene offers one piece of the puzzle, it is only one piece of many.

Meanwhile, the debate among breeders rages on, and myths and misinformation continue to surface. Some feel this mutation is a modifier, and not a causative gene; others see this mutation as the major factor but acknowledge there may be other, "protective" genes that determine whether a dog will develop VPCs. What is known is that this mutation leads to a loose connection between cardiac cells, and that Boxers affected by ARVC that have two copies of the mutated gene have on average higher numbers of VPCs than Boxers affected by ARVC that have only one copy of the mutated gene. More information on this debate will be added to this page as it develops; in the mean time, for simplicity's sake, we are calling this mutation "ARVC Mutation 1", or "ARVC-1".

Update - July 2010

The ARVC genetic research was accepted for publication in the Human Genetics journal (online before print). Following are some key points from the manuscript:

As part of an ongoing study of the heritability of canine ARVC, 300 pet boxer dogs over 1 year of age were prospectively recruited for participation. All dogs were evaluated with physical examination, electrocardiogram, echocardiogram, and a 24-h ambulatory electrocardiogram using a three-channel transthoracic system. Pedigrees were collected when available.

Diagnostic criteria for canine ARVC included the presence of [greater than or equal to] 500 VPCs of right ventricular origin/24 h (normal dogs have an average of 2/24 h) and, when present, syncope.... Dogs with echocardiographic abnormalities suggestive of congenital heart disease or dilated cardiomyopathy were excluded. Using these criteria, 65 boxer dogs were diagnosed as ARVC-affected. This included 30 males (18 castrated, 12 intact) and 35 females (16 spayed, 19 intact) with an average age of 7 years. Criteria for accepting a boxer dog as a control required a minimum age of 6 years, and a normal cardiovascular physical examination with [less than] 100 VPCs/24 h. One hundred canine DNA samples were also obtained from the laboratory bank of canine DNA collected from 11 different breeds of dogs as controls.

Genome-wide analysis (GWA) was performed with ... DNA from 46 boxer ARVC cases and 43 boxer controls. Only affected and control dogs with pedigrees were used for the GWA and participating dogs were specifically selected so that no dogs were related within a three generational pedigree.



Subsequently, sequences from 61 cases (42/46 samples from GWA that had sufficient amount of remaining DNA), 38 controls (38/43 from GWA) and 100 non-boxer (11 different breeds) dog controls were genotyped for the 8-bp deletion at the 30 UTR region of Striatin.



Dogs that were homozygous for the deletion ... had more severe disease based on VPCs number than heterozygous dogs. Homozygous dogs recorded 1,091-32,000 VPCs/24 h (median of 5,102) and heterozygous ARVC dogs 109-19,000 VPCs/24 h (median of 2,515).



Four dogs originally diagnosed with ARVC did not have the deletion.... [I]t is possible that the dogs were incorrectly phenotyped as affected and actually had other disease processes that mimic ARVC. An additional possibility is that, as in human beings, ARVC may be a disease of significant genetic heterogeneity in the dog. In human beings, more than 100 pathogenic variants have been identified in 8 genes at this time. It is possible that the canine form of ARVC may be associated with more than one genetic mutation and likely more than one gene. Although it is true that the boxer dog is a pure breed dog with a fairly closed gene pool, it has an estimated heterozygosity of approximately 47%. The development of more than one novel mutation is possible, especially given the significant genetic heterogeneity of the disease in human beings. ARVC in these four dogs (7% of the ARVC cases) may be due to a different, yet to be identified, genetic variant. In human beings, approximately 60% of ARVC cases do not have a mutation in a known disease causing gene.

Likewise, 11 of the 35 dogs classified as controls were found to be heterozygous for the deletion. In this study, we classified dogs as unaffected controls if they were at least 6 years of age and had less than 100 VPCs/24 h. Boxer ARVC is an adult onset disease with a variable age of onset. The diagnosis of canine ARVC has been reported in dogs as young as 1 year of age and as old as 13 years of age with a median age of onset of 6 years of age. It is possible that dogs with the deletion who were not yet demonstrating the ARVC phenotype will express the disease at an older age. The variant described in this study had an approximately 72% penetrance. In human beings, ARVC is a disease with age-related, relatively low penetrance and variable expressivity. In some kindreds with the autosomal dominant form of ARVC, the penetrance may be as low as 20-30%. Many individuals with a known genetic mutation will never develop clinically significant disease and even within the same family, some individuals will have a more benign disease course than others. Degree of penetrance may be somewhat dependent on the specific causative gene....

The incomplete penetrance and variability of expressivity in ARVC likely suggests the role of environmental factors and genetic modifiers in the presentation of this disease and supports further investigation of the second strongly associated region at 35-38.5 Mb.


Genetics of ARVC-1

There are two possible forms (or alleles) of the gene, the mutated, or abnormal, form (A) and normal form (a). Every Boxer has two alleles, inheriting one from each parent; the combinations can be two copies of the mutated gene (homozygous positive), two copies of the normal gene (negative), or one copy of each gene (heterozygous positive). Because ARVC is considered to be a dominant gene, there are no "carriers". However, it is important to note that not all Boxers who have one or two copies of the mutated gene will go on to develop ARVC - nor will all Boxers who are free of the mutation be free of ARVC.

mutated gene normal gene
Mutated Gene   
A
   Normal Gene
a

homozygous positive dog
Homozygous Positive Dog
(AA)

This dog has two copies of the mutated gene. It will pass a mutated gene on to every one of its puppies.

negative dog
Homozygous Normal Dog
(Negative - aa)

This dog has two copies of the normal gene. It cannot pass a mutated gene on to its offspring.

heterozygous positive dog
Heterozygous Positive Dog
(Aa)

This dog has one copy of the mutated gene, and one copy of the normal gene. It will pass a mutated gene to, on average, 50% of its puppies.

Below are the different ARVC-1 genetic combinations that can occur in Boxer breedings.

An important note: While the actual distribution of genes in an individual litter may stray from the expected (i.e., a heterozygous positive x negative breeding may produce 100% negative puppies), over a large number of litters the outcome will meet the expectations.

homozygous positive x homozygous positive
Homozygous Positive x Homozygous Positive
(AA x AA)
100% Homozygous Positive (AA)
homozygous positive x negative
Homozygous Positive x Negative
(AA x aa)
100% Heterozygous Positive (Aa)

homozygous positive x heterozygous positive
Homozygous Positive x Heterozygous Positive
(AA x Aa)
50% Homozygous Positive (AA)
50% Heterozygous Positive (Aa)
heterozygous positive x heterozygous positive
Heterozygous Positive x Heterozygous Positive
(Aa x Aa)
25% Homozygous Positive (AA)
50% Heterozygous Positive (Aa)
25% Negative (aa)

heterozygous positive x negative
Heterozygous Positive x Negative
(Aa x aa)
50% Heterozygous Positive (Aa)
50% Negative (aa)
negative x negative
Negative x Negative
(aa x aa)
100% Negative


Again, this test detects the presence of the mutation, not the presence of ARVC. Routine holter monitoring should be continued on all breeding stock, regardless of ARVC-1 test results. Early reports show that a significant portion of the breed possesses at least one mutated gene - we cannot at this point afford to eliminate all positive dogs, or even all homozygous positive dogs, from our breeding programs. Until we know more about other genes that may be involved in the development and expression of ARVC, holter numbers and longevity will still give us the best chances of reducing ARVC in the Boxer breed, especially that which causes sudden early death. While eliminating this mutation would mean we no longer have dogs with weak connections between cardiac cells (due to this mutation), if we place too much emphasis on this one test we run the risk of increasing the incidence of other, potentially more severe genetic problems in the breed.

There was an excellent article about a similar situation in Miniature Schnauzers, where over-emphasizing one gene had a devastating on the breed's health, published in Canine Review magazine. The article is available as a .pdf file:
Part 1
Part 2




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