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This family appears to have an early onset autosomal dominant (AD) RP. There is male to male transmission, which excludes X linked RP.1 Although the man‘s father was diagnosed at an older age this may be because the family was unaware of RP at that time. Once the family is aware of the condition and its presenting symptoms they may present earlier, as would appear to be the case with the girl in question. At age 4 years it is unlikely that there would be any abnormality detected on fundus examination.
RP genes and mutations screening
There are at least 13 genes that cause ADRP. These are listed in Table 1. An updated listing of retinal dystrophy genes is available on RetNet (http://www.sph.uth.tmc.edu/Retnet/home.htm) and OMIM (http://www3.ncbi.nlm.nih.gov/Omim/searchomim.html).
Genetic analysis of RP
Different approaches can be used to determine the genetic background of a disease depending on the type of samples available. When a family with several affected individuals is available, linkage analysis can be used to include or exclude gene loci of interest. Otherwise, for the more common scenario of sporadic cases, mutational analysis of candidate genes is used.
If several family members are available for testing and motivated, then a linkage analysis could be performed for the known loci. Definitely unaffected family members are also useful for this analysis. With just three affected members, it may not be possible to be certain which gene is involved, but it may be possible to exclude some loci. If there were a large number of affected individuals (that is, 10 people) and the analysis had excluded known loci, then it would be possible to do a genome-wide scan for the identification of a new RP locus. I would prioritise the gene loci associated with early onset RP and ADRP. Even though there was one family member with a late diagnosis, as clinically this sounds like an early onset disease.
Although it would be possible to screen each of the genes for mutations, this would be a large undertaking and the resources are usually not there to do it completely. In this case only a few candidate genes such as rhodopsin and RDS would be looked at. Determining the genetic background of the disease is important to better understand its progression. However, the great genetic heterogeneity of RP had not been anticipated and most centres do not have the infrastructure to provide molecular analysis of all the known RP genes.
Availability and cost of DNA testing: this is the million dollar question!
Where to get the testing done depends on where you are and who you collaborate with. When you send samples from the same family to different laboratories it is important that this is discussed a priori. This can be a very frustrating scenario and can lead to potential conflicts as these tests are usually still done on a research basis and are very time consuming.
Who pays? Very few health systems are willing to pay for DNA testing. Some laboratories have limited funds for semi-research DNA testing. I don‘t think at this point that the quality of the diagnosis we offer warrants billing patients directly. By this I mean that the genetic characterisation of the disease is incomplete. In many cases we will not find the gene mutation involved and at present we cannot give patients a full interpretation of the results.
How do you know a base change is a mutation and is disease causing?
Distinguishing between disease causing mutations and benign polymorphisms in RP (or any disease) genes can be quite difficult. Just because a mutation has been reported in the literature doesn‘t prove it is pathogenic and that is where having a family to study becomes useful. A family allows the assessment of the segregation of the defect to be identified and the determination of whether it segregates with the disease status or not. This family definitely would allow assessment of segregation for the sequence change with the disease phenotype. Ethnically matched normal population controls should also be tested.
In this case that should do it.
How we could change management?
Definitely attempt an ERG although she is age 4 years. At 7 years you can try a Goldmann visual field examination. Examining other affected family members would allow a better understanding of the phenotype in this family. I am not against early diagnosis as it provides longitudinal information that can be useful in future management opportunities.
A night light is certainly worth a try but is also psychological support to the child. It‘s not a treatment it‘s a tool. I usually tell the children, parents, and whoever else is involved that they should always have a pocket flashlight. It can be very handy. They can keep it by their pillow or on their night table and it usually brings reassurance in the dark. Do night lights cause myopia? This is a controversial area,2,3 although I wouldn‘t worry about it personally. This is a separate issue from the RP and I think the RP management is more important.
Predictive DNA testing
It all depends why the family wants to do it. I often use electrophysiology testing more than molecular testing in this type of case, unlike DNA testing in glaucoma. The main issues in adults relate to insurance; however, in children issues are more complex.
Issues in children include fear of the child and of parents. However, this could also turn into good guidance. Molecular testing provides evidence for a risk factor, the diagnosis remains clinical.4
ERG compared with DNA testing
The reliability and predictiveness of the tests differ and it depends at what age it is done. In the case of ERG, performing it too early can lead to a false negative, whereas in the case of molecular testing a gene with incomplete penetrance can yield a false positive. In other words, a gene mutation reflects a risk factor for the development of the disease but it does not imply that the patient will definitely develop the disease. Further research is needed to clarify the penetrance and expressivity of the different mutations. You need to explain both sides to the family. Usually I determine the age at which we do the ERG based on the age of onset of the symptoms and the family history. In this case I would definitely do an ERG.
Some ethicists say it is unethical to do DNA testing but do not raise the issue of doing an ERG
I disagree, it depends what you want to know, the expectations of the family, and the context and the disease. You need to tailor your approach, this is not one stop shopping! No one solution will be good for all patients and families. The key is to discuss all the issues with the family and to get their opinions on the “ethical issues.” The first things I try to clarify is what they understand about the disease and their fears, then “what do they think of the status of the unaffected person?” What does knowing otherwise involve? I always make sure there is another person from our team present as a witness and document what was said, as misinterpretations are common especially when there is fear. I think the key here is guidance by the treating doctor in relation to implications and resources.