Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era
Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The <i>LRRK2</...
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MDPI AG
2021-03-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/12/3/430 |
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doaj-86a723ef25544c289ab0bb194335e4882021-03-18T00:04:01ZengMDPI AGGenes2073-44252021-03-011243043010.3390/genes12030430Hunting for Familial Parkinson’s Disease Mutations in the Post Genome EraSteven R. Bentley0Ilaria Guella1Holly E. Sherman2Hannah M. Neuendorf3Alex M. Sykes4Javed Y. Fowdar5Peter A. Silburn6Stephen A. Wood7Matthew J. Farrer8George D. Mellick9Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, QLD 4111, AustraliaDjavad Mowafhagian Centre for Brain, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaDjavad Mowafhagian Centre for Brain, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaGriffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, QLD 4111, AustraliaGriffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, QLD 4111, AustraliaGriffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, QLD 4111, AustraliaCentre for Clinical Research, University of Queensland, Brisbane, QLD 4029, AustraliaGriffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, QLD 4111, AustraliaDjavad Mowafhagian Centre for Brain, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaGriffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, QLD 4111, AustraliaParkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The <i>LRRK2</i> p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the <i>KCNJ15</i> p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the <i>SIPA1L1</i> p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.https://www.mdpi.com/2073-4425/12/3/430familialmulti-incidentparkinsonismmovement disorderexomemutation |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Steven R. Bentley Ilaria Guella Holly E. Sherman Hannah M. Neuendorf Alex M. Sykes Javed Y. Fowdar Peter A. Silburn Stephen A. Wood Matthew J. Farrer George D. Mellick |
| spellingShingle |
Steven R. Bentley Ilaria Guella Holly E. Sherman Hannah M. Neuendorf Alex M. Sykes Javed Y. Fowdar Peter A. Silburn Stephen A. Wood Matthew J. Farrer George D. Mellick Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era Genes familial multi-incident parkinsonism movement disorder exome mutation |
| author_facet |
Steven R. Bentley Ilaria Guella Holly E. Sherman Hannah M. Neuendorf Alex M. Sykes Javed Y. Fowdar Peter A. Silburn Stephen A. Wood Matthew J. Farrer George D. Mellick |
| author_sort |
Steven R. Bentley |
| title |
Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era |
| title_short |
Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era |
| title_full |
Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era |
| title_fullStr |
Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era |
| title_full_unstemmed |
Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era |
| title_sort |
hunting for familial parkinson’s disease mutations in the post genome era |
| publisher |
MDPI AG |
| series |
Genes |
| issn |
2073-4425 |
| publishDate |
2021-03-01 |
| description |
Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The <i>LRRK2</i> p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the <i>KCNJ15</i> p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the <i>SIPA1L1</i> p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases. |
| topic |
familial multi-incident parkinsonism movement disorder exome mutation |
| url |
https://www.mdpi.com/2073-4425/12/3/430 |
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