| 1. |
- Rödström, E. Ygland, et al.
(författare)
-
Genomic analyses of a large Swedish multi-incident kindred with autosomal dominant Parkinson’s disease with dementia
- 2023
-
Ingår i: Parkinsonism & Related Disorders. - 1353-8020. ; 113:Supp, s. 28-29
-
Konferensbidrag (refereegranskat)abstract
- Background:The known genetic causes for Parkinson’s disease (PD) onlyexplain a small proportion of the familial aggregation of PD. Despiteintensive efforts by researchers internationally, identifying and confirmingadditional monogenic causes for PD has been difficult.Methods:We examined 16 members of a large family with multi-incidentPD 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 familymembers and known gene functions. WES data from 843 PD cases and 885controls were screened for the two most highly ranked candidate variantsand used for gene burden analysis.Results:Clinically, all affected family members had typical PD withcognitive decline. Two affected individuals showed typical PD neuropathology. Out of nine genetic variants identified, we highlighted two as goodcandidates for causing this family’s PD. However, co-segregation with PDwas imperfect and this study was complicated by the fact that somegenotyped family members showed mild motor symptoms of uncertaincause, or cognitive decline without apparent motor dysfunction. Geneburden analysis showed no difference between cases and controls in thefrequency 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 identifiedin one additional familial PD proband from the case series and geneticvariants in the other top-candidate gene had previously been associatedwith an increased risk for PD in humans.Conclusions: Our study was not able to determine a single high-impactvariant as the cause of PD with cognitive decline in the family despitedetailed clinical and genetic assessments, but we nominate two potentialcandidate variants. Reduced penetrance and phenocopies may complicategenomic studies of families with PD.
|
|
| 2. |
- Ilinca, A., et al.
(författare)
-
MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor
- 2021
-
Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke. Methods We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses. Results Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease. Conclusions Our data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.
|
|
| 3. |
- Kafantari, E., et al.
(författare)
-
Whole exome sequencing of familial, combined or complex dystonia
- 2023
-
Ingår i: Parkinsonism & Related Disorders. - 1353-8020. ; 113:Supp, s. 65-66
-
Konferensbidrag (refereegranskat)abstract
- Background: To determine the usefulness of whole exome sequencing(WES) in the diagnostic evaluation of patients and small families withfamilial, combined and/or complex forms of dystonia identified from anadult neurology clinic at a tertiary center, and to set up a computationalpathway for the bioinformatics analyses.Methods: By mail, we contacted all 347 patients from our department whoduring a 4-year period had an ICD-10 diagnosis of dystonia. Of these, 122were re-examined within our research study. Patients who had combinedand/or complex dystonia phenotypes and patients who reported closefamily members with dystonia were examined by WES. Differentcomputational approaches followed (co-segregation or trio analysis,filtering variants based on an in-house gene list with more than 500 dystonia nuclear and mitochondrial genes etc.). Copy number variants (CNVs)were also detected by using in-silico tools.Results: Re-examination revealed that 11 of 122 (9.0%) of patients hadother disorders. Of the remaining 111 patients, fourteen had familial, combined or complex dystonia phenotypes starting at mean 37.6 (SD 14.9)years and were analysed by WES. For 5 of these, a definite or candidatemonogenic disease cause was identified (table).The diagnostic yield in this project was 35,7% with positive or likely positive findings. Two of 5 patients had variants that had been described previously (40%) and the remaining 3 carried putatively pathogenic variants (60%).Conclusions: Candidate disease-causing variants were identified in 5 out of 14 cases investigated, all these had combined or complex dystonia and relatively young onset (mean 22.3, SD 11.3 years). CNV analysis is relevant in the genetic workup of familial/combined/complex dystonia.
|
|
