A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease

TY - JOUR

T1 - A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease

AU - Kun-Rodrigues, Celia

AU - Ganos, Christos

AU - Guerreiro, Rita

AU - Schneider, Susanne A

AU - Schulte, Claudia

AU - Lesage, Suzanne

AU - Darwent, Lee

AU - Singleton, Andrew

AU - Bhatia, Kailash

AU - Bras, Jose

AU - International Parkinson Disease Genomics Consortium (IPDGC)

N1 - © The Author 2015. Published by Oxford University Press.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddv376

DO - 10.1093/hmg/ddv376

M3 - SCORING: Journal article

C2 - 26362251

VL - 24

SP - 6711

EP - 6720

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 23

ER -