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Genomic analyses of a large Swedish multi-incident kindred with autosomal dominant Parkinson’s disease with dementia

Rödström, E. Ygland LU ; Soto-Beasley, A. ; Englund, E. LU orcid ; Kafantari, E. LU ; Dickson, D.W. ; Wszolek, Z.K. ; Puschmann, A. LU orcid and Ross, O.A. (2023) In Parkinsonism & Related Disorders 113(Supp). p.28-29
Abstract
Background:The known genetic causes for Parkinson’s disease (PD) only
explain a small proportion of the familial aggregation of PD. Despite
intensive efforts by researchers internationally, identifying and confirming
additional monogenic causes for PD has been difficult.
Methods:We examined 16 members of a large family with multi-incident
PD and dementia. Eight members were examined by whole exome (WES)
or whole genome sequencing. Rare variants co-segregating with the disease were evaluated based on their distribution in additional family
members and known gene functions. WES data from 843 PD cases and 885
controls were screened for the two most highly ranked candidate variants
and used for gene burden... (More)
Background:The known genetic causes for Parkinson’s disease (PD) only
explain a small proportion of the familial aggregation of PD. Despite
intensive efforts by researchers internationally, identifying and confirming
additional monogenic causes for PD has been difficult.
Methods:We examined 16 members of a large family with multi-incident
PD and dementia. Eight members were examined by whole exome (WES)
or whole genome sequencing. Rare variants co-segregating with the disease were evaluated based on their distribution in additional family
members and known gene functions. WES data from 843 PD cases and 885
controls were screened for the two most highly ranked candidate variants
and used for gene burden analysis.
Results:Clinically, all affected family members had typical PD with
cognitive decline. Two affected individuals showed typical PD neuropathology. Out of nine genetic variants identified, we highlighted two as good
candidates for causing this family’s PD. However, co-segregation with PD
was imperfect and this study was complicated by the fact that some
genotyped family members showed mild motor symptoms of uncertain
cause, or cognitive decline without apparent motor dysfunction. Gene
burden analysis showed no difference between cases and controls in the
frequency of potentially deleterious variants in the top-candidate genes.
Nonetheless, factors that could indicate an impact of either of the two topcandidate genetic variants were found as one of the variants was identified
in one additional familial PD proband from the case series and genetic
variants in the other top-candidate gene had previously been associated
with an increased risk for PD in humans.
Conclusions: Our study was not able to determine a single high-impact
variant as the cause of PD with cognitive decline in the family despite
detailed clinical and genetic assessments, but we nominate two potential
candidate variants. Reduced penetrance and phenocopies may complicate
genomic studies of families with PD. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Parkinsonism & Related Disorders
volume
113
issue
Supp
article number
P 062 (GPT)
pages
28 - 29
publisher
Elsevier
ISSN
1353-8020
DOI
10.1016/j.parkreldis.2023.105600
language
English
LU publication?
yes
id
6d71d128-59c0-478b-8764-67cae0171d89
date added to LUP
2023-08-31 21:59:57
date last changed
2023-09-01 09:53:54
@misc{6d71d128-59c0-478b-8764-67cae0171d89,
  abstract     = {{Background:The known genetic causes for Parkinson’s disease (PD) only<br/>explain a small proportion of the familial aggregation of PD. Despite<br/>intensive efforts by researchers internationally, identifying and confirming<br/>additional monogenic causes for PD has been difficult.<br/>Methods:We examined 16 members of a large family with multi-incident<br/>PD and dementia. Eight members were examined by whole exome (WES)<br/>or whole genome sequencing. Rare variants co-segregating with the disease were evaluated based on their distribution in additional family<br/>members and known gene functions. WES data from 843 PD cases and 885<br/>controls were screened for the two most highly ranked candidate variants<br/>and used for gene burden analysis.<br/>Results:Clinically, all affected family members had typical PD with<br/>cognitive decline. Two affected individuals showed typical PD neuropathology. Out of nine genetic variants identified, we highlighted two as good<br/>candidates for causing this family’s PD. However, co-segregation with PD<br/>was imperfect and this study was complicated by the fact that some<br/>genotyped family members showed mild motor symptoms of uncertain<br/>cause, or cognitive decline without apparent motor dysfunction. Gene<br/>burden analysis showed no difference between cases and controls in the<br/>frequency of potentially deleterious variants in the top-candidate genes.<br/>Nonetheless, factors that could indicate an impact of either of the two topcandidate genetic variants were found as one of the variants was identified<br/>in one additional familial PD proband from the case series and genetic<br/>variants in the other top-candidate gene had previously been associated<br/>with an increased risk for PD in humans.<br/>Conclusions: Our study was not able to determine a single high-impact<br/>variant as the cause of PD with cognitive decline in the family despite<br/>detailed clinical and genetic assessments, but we nominate two potential<br/>candidate variants. Reduced penetrance and phenocopies may complicate<br/>genomic studies of families with PD.}},
  author       = {{Rödström, E. Ygland and Soto-Beasley, A. and Englund, E. and Kafantari, E. and Dickson, D.W. and Wszolek, Z.K. and Puschmann, A. and Ross, O.A.}},
  issn         = {{1353-8020}},
  language     = {{eng}},
  note         = {{Conference Abstract}},
  number       = {{Supp}},
  pages        = {{28--29}},
  publisher    = {{Elsevier}},
  series       = {{Parkinsonism & Related Disorders}},
  title        = {{Genomic analyses of a large Swedish multi-incident kindred with autosomal dominant Parkinson’s disease with dementia}},
  url          = {{http://dx.doi.org/10.1016/j.parkreldis.2023.105600}},
  doi          = {{10.1016/j.parkreldis.2023.105600}},
  volume       = {{113}},
  year         = {{2023}},
}