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Rare variants of the 3'-5' DNA exonuclease TREX1 in early onset small vessel stroke.
McGlasson, Sarah; Rannikmäe, Kristiina; Bevan, Steven; Logan, Clare; Bicknell, Louise S; Jury, Alexa; Jackson, Andrew P; Markus, Hugh S; Sudlow, Cathie; Hunt, David P J.
Afiliação
  • McGlasson S; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
  • Rannikmäe K; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Bevan S; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
  • Logan C; Stroke Research Group, Department of Clinical Neurosciences, Cambridge University, Cambridge, CB2 2PY , UK.
  • Bicknell LS; Joseph Banks Laboratories, University of Lincoln, Lincoln, LN6 7DL, UK.
  • Jury A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Jackson AP; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
  • Markus HS; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Hunt DPJ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Wellcome Open Res ; 2: 106, 2017.
Article em En | MEDLINE | ID: mdl-29387804
ABSTRACT

Background:

Monoallelic and biallelic mutations in the exonuclease TREX1 cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of TREX1 in small vessel stroke is warranted.

Methods:

We sequenced the TREX1 gene in an exploratory cohort of patients with lacunar stroke (Edinburgh Stroke Study, n=290 lacunar stroke cases). We subsequently performed a fully blinded case-control study of early onset MRI-confirmed small vessel stroke within the UK Young Lacunar Stroke Resource (990 cases, 939 controls).

Results:

No patients with canonical disease-causing mutations of TREX1 were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of TREX1 and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of TREX1 in a larger and MRI-confirmed patient cohort, the UK Young Lacunar Stroke Resource, identified heterozygous rare variants in 2.1% of cases and 2.3% of controls. No association was observed with stroke risk (odds ratio = 0.90; 95% confidence interval, 0.49-1.65 p=0.74). Similarly no association was seen with rare TREX1 variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91).

Conclusions:

No patients with early-onset lacunar stroke had genetic evidence of a TREX1-associated monogenic microangiopathy. These results show no evidence of association between rare variants of TREX1 and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the TREX1 gene in patients with early onset lacunar stroke is therefore unlikely to be of diagnostic utility, in the absence of syndromic features or family history.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Wellcome Open Res Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Wellcome Open Res Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Reino Unido