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- 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
(författare)
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Genetic mechanisms for stroke in young adults. A clinical perspective.
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A range of cardiovascular risk factors associated with stroke are known, but they do not explain all cases of stroke. Genetic factors can be responsible for certain forms of stroke, and are further investigated in this thesis. The aims of this thesis were to study the occurrence of familial clustering of stroke, compile known stroke-associated genetic conditions for diagnostic and research genetic testing, and examine patients and families with apparently hereditary forms of stroke, focusing on patients who developed stroke at younger age.Based on data from Lund Stroke Register (LSR), patients with a first stroke episode before age 56 years were investigated regarding familial history for stroke and familial clustering of stroke compatible with possible monogenic disease (Paper I). The Online Mendelian Inheritance in Man (OMIM) database was used to systematically compile known stroke related genes, and for all these genes the clinical type of stroke was retrieved from original literature. Stroke gene panels for new generation sequencing were created (Paper II), and were applied to investigate 23 stroke families for known genetic causes of stroke (Papers III and IV). Detailed genetic investigations of larger families with seemingly hereditary stroke by whole exome sequencing (WES), whole genome sequencing (WGS) and conventional Sanger sequencing (Sg) were performed. Pathology of brain and skin vessels was analyzed.Paper I: Ten percent of 4,103 LSR patients were younger than 56 years. Of these, 47% (159 probands) reported a positive family history for stroke. Results revealed that 18% of the patients who were under 56 years at their first stroke episode, and with a positive familial history of stroke, did not have any of the usual vascular risk factors.Paper II: Stroke gene panels for use in clinical diagnostics and for research purposes were compiled. A total of 214 genes documented in OMIM were identified. One hundred-twenty genes were associated with clinically documented episodes of stroke (stroke gene panel 1). Sixty-two additional genes related to stroke, but without a reported case of a stroke episode in humans, were compiled for stroke gene panel 2. We included in stroke gene panel 3 stroke-related genes previously detected by genome-wide association studies. Clinical descriptions for the phenotypes associated with each gene were collected, to facilitate correct interpretation of the ample data generated by new generation sequencing analyses.Papers III and IV: WES of 23 probands and validation by Sg in affected and unaffected relatives identified pathogenic or possibly pathogenic genetic variants in 6 of the families, but the pathogenicity of only one was proven beyond doubt. For two larger families with embolic stroke of undetermined source at before 46 years of age and without any suspected variation in known stroke genes, we identified variants in genes not previously associated with stroke; GPR142 for one of the families and in PTPRN2, LRRC1, SLC7A10, IKBKB, and OXGR1 for the other family. In one large kindred with a novel entity with autosomal dominant small vessel disease, stroke, and tremor, a variant in the MAP3K6 gene was identified. Also this gene had not previously been associated with stroke. Pathology showed abnormalities in blood vessels of the brain and the skin and we suggest a pathomechanism involving vascular endothelial growth factor, based on what presently is known about the function of MAP3K6.WES of stroke patients 55 years or younger has presently a low diagnostic yield, but remains a practical method for clinical diagnostics of known stroke related disease. In research, whole exome or genome sequencing analyses of families may identify novel disease genes and new mechanisms for stroke.
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| 3. |
- Ilinca, Andreea, et al.
(författare)
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Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke
- 2020
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Ingår i: Stroke. - 1524-4628. ; 51:4, s. 1056-1063
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Tidskriftsartikel (refereegranskat)abstract
- Backgrounds and Purpose- Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods- We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results- Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2:c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142:c.148C>G (p.Leu50Val), and PTPRN2:c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10c.1294dupG (p.Val432fs), IKBKB: c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions- Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
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