Because of the extreme variety of mutations in the PARKIN gene, screening is complex and requires a combination of sequencing to detect point mutations as well as dosage experiments for exon rearrangements (48,124). Before undertaking a genetic test for PARKIN mutations, however, it is important to ask the following questions: Is the indication appropriate? Will the result be interpretable?
There are two reasons to look for PARKIN mutations. The first is to confirm a diagnosis. Given the frequency of dystonia in patients with PARKIN mutations, they may be difficult to distinguish from those with dopa-responsive dystonia. Correct diagnosis is also important for patients with juvenile onset, because it can affect prognosis and treatment; patients with PARKIN mutations are, for example, good candidates for deep brain stimulation. PARKIN should also be tested in view of genetic counselling. The identification of PARKIN as the cause of their disease is reassuring for patients and their sibs, since it excludes the high risk recurrence in subsequent generations by autosomal dominant transmission. In situations where the spouses are related, testing should also be performed. If both are carriers, prenatal diagnosis can be envisaged.
Before testing for PARKIN mutations, however, the probability of obtaining a positive test result should be evaluated. At present, patients with early-onset parkinsonism and a good response to treatment appear to be the most appropriate candidates for PARKIN analysis. In isolated cases, the yield is over 25% when onset is before the age of 30, although it drops sharply with age, particularly at 40 or above. When two or more sibs are affected, the yield exceeds 50%, even in patients who are 45- or 50-years. With later onset, the proportion will again decline.
The results of genetic testing for PARKIN mutations, as for other autosomal recessive disorders, are not easy to interpret. It is crucial that all coding exons be analysed for point mutations by sequencing and for exon rearrangements by gene dosage. In this case, the absence of mutations strongly excludes the possibility of PARKIN-related disease. The presence of one or more sequence variants is more difficult to interpret. When two different mutations are found, they must be in trans (affecting both copies of the gene) before it can be concluded that they are responsible for the phenotype. This is often difficult when two consecutive exons (e.g., exons 3 and 4) are deleted, since both can be deleted on the same allele or each on a different allele. However, this ambiguity can be resolved by RT-PCR analysis or when other family members can be tested. Further complicating analysis, the PARKIN gene carries many rare polymorphisms that vary among populations and are difficult to distinguish from pathogenic mutations. The fact that a sequence variant, even in the coding region, is not found on hundreds of control chromosomes is not sufficient proof that it is a disease-causing mutation.
These problems underline the importance of good communication between the practitioner requesting a genetic test and the biologist performing the analysis. Patients must be sure to receive reliable information, including a clear understanding of its limits.
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