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

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.