GENETICS OF ARVD
There is a lot of evidence that ARVD is a genetic, heritable condition where an affected person has a chance of passing on a specific gene change to his or her children. There is also some evidence that ARVD could result from an infection of the heart muscle. One or both theories could be correct. For instance, an infection in someone with a certain genetic make-up could cause ARVD.
In general, someone who inherits a gene change or mutation for ARVD has inherited a genetic predisposition to developing ARVD. A single gene change is usually not sufficient for the development of ARVD. We think that for most individuals, additional factors such as other genes, athletic lifestyle, exposure to certain viruses, etc. are needed for an individual to actually develop signs and symptoms of ARVD. This is an area of very active research and we have a lot to learn about all the factors that can cause ARVD.
To help explain the inheritance of ARVD, let us back up and explain some concepts of biology. Our bodies are made up of cells that contain DNA. The DNA is a string of messages that we call genes. Genes are like sentences in that certain letters are put together to make a code that are the instructions for telling our bodies how to look and function. If a letter or letters from a sentence are missing or added in the wrong place, the genetic sentence will not make sense and can result in genetic disorders like ARVD. These gene changes can be passed on from one generation to the next. In general you have two copies of every gene, one from your mother and one from you father.
ARVD can be inherited in 2 different ways: autosomal dominant inheritance with reduced penetrance and autosomal recessive inheritance. In autosomal dominant inheritance, a person with a gene change predisposing them to ARVD has a 50% chance of passing on that same predisposition to their child. We know that not everyone who inherits a gene change associated with ARVD will develop ARVD. This is called “reduced penetrance”. Among people in a family who get ARVD there is variation in the severity of the disease and the age that ARVD presents itself. We are working hard to figure out what genetic and other factors predict which people with a genetic change go on to develop ARVD.
In autosomal recessive inheritance, an individual has to have two copies of a gene associated with ARVD to get the disease. A person has a 25% chance of inheriting both copies of the gene changes responsible for ARVD (one from dad and one from mom). Each parent “carries” a gene change but does not have ARVD. This type of pattern is seen in Naxos disease, a variant of ARVD predominantly seen in Greece. Autosomal dominant appears to be the most common pattern of inheritance. There are some families who carry more than one genetic change.
| Genetics of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy | |||
| Gene (Symbol) | Locus | Inheritance | Notes |
| 11%-43% | |||
| Plakophilin-2 (PKP2)* | 12q11 | AD/AR | 1 family with recessive mutation has been reported without hair or skin abnormalities |
| Desmoglein-2 (DSG2)* | 18q12 | AD/AR | 10%-12% |
| 6%-16% | |||
| Desmoplakin (DSP)* | 6p24 | AD | ARVD/C or arrhythmogenic left ventricular cardiomyopathy |
| Desmocollin-2 (DSC2)* | 18q12 | AD | 1%-5% |
| Transforming growth factor-beta3 (TGF B3) | 14q24.3 | AD | 2 families worldwide |
| Plakoglobin (JUP) | 17q21 | AD | ARVD/C without cutaneous abnormalities (German ancestry - one family) |
| Plakoglobin (JUP) | 17q21 | AR | ARVD/C, palmoplantar keratoderma, woolly hair (Greek Ancestry) - "Naxos" |
| Desmoplakin (DSP) | 6p24 | AR | woolly hair, palmoplantar keratoderma, left-sided dilated cardiomyopathy - "Carvajal" |
| catecholaminergic polymorphic ventricular tachycardia | |||
| Cardiac Ryanodine Receptor (RYR2) | 1q42 | AD | Atypical form of ARVD |
| fully penetrant, sex-influenced form of ARVD/C | |||
| Transmembrane protein 43 (TMEM43) | 3p25 | AD | Newfoundland ancestry |
* Genetic testing available in the US
AD = Autosomal Dominant
AR = Autosomal Recessive
Please note that this information is only accurate as of April 2008 and may change as additional genetic research is performed
GENETIC TESTING
Clinical genetic testing for plakophilin-2, desmoplakin, desmoglein-2, and desmocollin-2 is now available in the United States. Plakophilin-2 testing is available through the DNA Diagnostic Laboratory at Johns Hopkins. Additional information can be found at http://www.hopkinsmedicine.org/dnadiagnostic/. Clinical testing for plakophilin-2, desmoplakin, desmoglein-2, and desmocollin-2 is available through Harvard Laboratory for Molecular Medicine. Additional information can be found at http://www.hpcgg.org/. The Harvard lab does not bill insurance companies. In addition, The Hospital of Sick Kids in Toronto, Canada is also offering clinical testing for plakophilin-2, desmoplakin, desmoglein-2, and desmocollin-2. Additional information can be found at http://www.sickkids.ca/molecular/. If you are interested in finding out more about genetic testing for ARVD, please contact one of our genetic counselors at 410-502-7161 for more information. We are happy to work with you, your physicians, and your insurance company in understanding the risks, benefits, and limitations of genetic testing in your specific situation. There are many research laboratories that offer testing on a research basis, however, many of these labs are unable to provide results or require clinical confirmation of a research result. There are some institutions outside of the United States (Canada, France, Netherlands, and Germany) that offer clinical testing for plakophilin-2, ryanodine receptor, desmoplakin, desmoglein-2, and desmocollin-2. We strongly recommend that you meet with a genetic counselor (www.nsgc.org) beforehand to discuss the benefits, risks, and limitations of genetic testing. Interpretation of genetic test results for ARVD can be quite complex.