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.
Highlights
Cerebral small vessel disease (SVD) causes a quarter of all strokes and is the most common pathology underlying vascular cognitive decline and dementia[1]
Rare TREX1 variants can decrease exonuclease activity To confirm that rare variants with high Combined Annotation Dependent Depletion (CADD) scores exert a deleterious effect on protein function, we evaluated the effect of rare variants on TREX1 exonuclease activity with a high C-score from each group
One possibility is that mutations in genes that cause monogenic small vessel diseases, such as NOTCH3, HTRA1, COL4A1 and TREX1, might confer risk for sporadic lacunar stroke
Summary
Cerebral small vessel disease (SVD) causes a quarter of all strokes and is the most common pathology underlying vascular cognitive decline and dementia[1]. Dominant missense mutations in COL4A1 and COL4A2 cause rare familial forms of cerebral SVD6, and common variants in the same genes are associated with sporadic cerebral small vessel disease[3]. Biallelic mutations with loss of enzymatic function can cause Aicardi-Goutières’ Syndrome (AGS), a neonatal onset brain disorder with prominent microangiopathy[8,9] and features of activated innate immunity[10] Both genetic cerebral microangiopathies are associated with aberrant innate immune pathways, in particular dysregulation of the type I interferon pathway[10,11]. Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of TREX1 in small vessel stroke is warranted. 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. Routine sequencing of the TREX1 gene in patients with early onset lacunar stroke is unlikely to be of diagnostic utility, in the absence of syndromic features or family history
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