ERANET 1 NEURON 3: Identification of copy number variants in familial and pathologically proven PD

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One of the major initial impacts of the human genome project was how little we understood about genomic diversity. Over the past 2-3 years it has become clear that there is tremendous variation in the numbers of copies of a large proportion of the human genome. There are some striking examples of copy numbers leading to human disease. The best characterised in neurological disease is the rearrangements around PMP22 giving rise to CMT1a and hereditary liability to pressure palsies. In Parkinson’s disease, of the currently identified genes,rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-synuclein duplication or triplication is the commonest mutational mechanism. Copy number variation (CNVs) can be considered in 2 broad ways. First there are rare occurrences (as above) where the duplication or deletion of genomic region may lead to a highly penetrant ‘mendelian’ form of disease. In the second, there is the potential role of ‘common’ rearrangements in susceptibility to disease. In the case of PD the rearrangementslisted above were all found after classical positional cloning strategies had identified them as PD genes and it was during the genetic characterisation of these genes that the rearrangements were demonstrated. Recent advances in genetic technologies allows for a rapid, robust genome wide search for CNVs. We plan to screen our series of patients for CNVs. In essence we will look in our recessive families for CNV, with particular emphasis on homozygous rearrangements. This work complements the objectives of subproject 2. We are also aware that single heterozygous rearrangements can cause autosomal dominant disease (eg a-syn). Therefore, in parallel with subproject 1 we will interrogate our AD PD families. Finally the role of ‘common’ CNVs has not been assessed in PD and we will adopt a genome wide search in 400 cases of sporadic pathologically proven PD.