| 1. |
- Gorcenco, Sorina, et al.
(författare)
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New generation genetic testing entering the clinic
- 2020
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Ingår i: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 73, s. 72-84
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Tidskriftsartikel (refereegranskat)abstract
- New generation sequencing (NGS) genetic testing is a powerful diagnostic tool and is increasingly used in the clinical workup of patients, especially in unusual presentations or where a positive family history suggests heritable disease. This review addresses the NGS technologies Targeted sequencing (TS), Whole exome sequencing (WES), Whole genome sequencing (WGS), and the use of gene panels or gene lists for clinical diagnostic purposes. These methods primarily assess nucleotide sequence but can also detect copy number variants and many tandem repeat expansions, greatly simplifying diagnostic algorithms for movement disorders. Studies evaluating the efficacy of NGS in diagnosing movement disorders have reported a diagnostic yield of up to 10.1% for familial and 15.7% for early-onset PD, 11.7–37.5% for dystonia, 12.1–61.8% for ataxia/spastic paraplegia and 11.3–28% for combined movement disorders. Patient selection and stringency in the interpretation of the detected variants and genotypes affect diagnostic yield. Careful comparison of the patient's or family's disease features with the previously reported phenotype associated with the same variant or gene can avoid false-positive diagnoses, although some genes are implicated in various phenotypes. Moving from TS to WES and WGS increases the number of patients correctly diagnosed, but for many patients, a genetic cause cannot be identified today. However, new genetically defined entities are discovered at rapid pace, and genetic databases and our knowledge of genotype-phenotype correlations expand steadily. We discuss the need for clear communication of genetic results and suggest a list of aspects to consider when reporting neurogenetic disorders using NGS testing.
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| 2. |
- Ilinca, Andreea, et al.
(författare)
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MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor
- 2021
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Ingår i: Neurology: Genetics. - 2376-7839. ; 7:1
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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.
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| 3. |
- Ilinca, Andreea, et al.
(författare)
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Updated Stroke Gene Panels : Rapid evolution of knowledge on monogenic causes of stroke
- 2023
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 31:2, s. 239-242
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Tidskriftsartikel (refereegranskat)abstract
- This article updates our previous Stroke Gene Panels (SGP) from 2017. Online Mendelian Inheritance in Man and PubMed were searched. We divided detected genes into two SGP groups, SGP1: genes reported in at least one person with stroke and associated with one or more clinical subgroups: large artery atherosclerotic, large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection or occlusion), cerebral small vessel diseases, cardio-embolic (arrhythmia, heart defect, cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma, arteriovenous malformations) and metabolism disorders; and SGP2: genes related to diseases that may predispose to stroke. We identified 168 SGP1 genes, 70 of these were validated for clinical practice. We also detected 72 SGP2 genes. Nine genes were removed because of conflicting evidence. The number of genes increased from 168 to 240 during 4.5-years, reflecting a dynamic evolution and the need for regular updates for research and clinical use.
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