Abstract
Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent–child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein–protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes.
Highlights
The detailed aetiology of Parkinson’s disease (PD) remains largely unknown, data suggest the disease may be triggered through different mechanisms: protein inclusions accumulation, diminished mitochondrial activity, proteasomal/ lysosomal dysfunction and impaired dopamine production [1]
Four of the variants identified have been previously described in population databases: the variants in EPPK1, COL12A1, PEPD and SLC52A1 have low frequencies ranging from 0.00003 to 0.003 in Exome Aggregation Consortium (ExAC)
Human Molecular Genetics, 2015, Vol 24, No 23 | 6715. This is the first study to systematically screen for de novo mutations in early-onset sporadic PD using parent–proband trios
Summary
The detailed aetiology of Parkinson’s disease (PD) remains largely unknown, data suggest the disease may be triggered through different mechanisms: protein inclusions accumulation, diminished mitochondrial activity, proteasomal/ lysosomal dysfunction and impaired dopamine production [1]. An increasing number of publications show a strong genetic component for PD. Genome-wide association studies (GWAS) have significantly contributed to a more comprehensive knowledge of the risk loci involved in PD [2]. Despite these results, there is still a large number of sporadic, early-onset cases that carry no mutation in the known PD genes. There is still a large number of sporadic, early-onset cases that carry no mutation in the known PD genes These individuals have, in many cases, a form of disease that is indistinguishable from genetically linked disease
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