Rare variants of the 3'-5' DNA exonuclease in early onset small vessel stroke.

Monoallelic and biallelic mutations in the exonuclease cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of in small vessel stroke is warranted. We sequenced the 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). No patients with canonical disease-causing mutations of were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of 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 variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91). No patients with early-onset lacunar stroke had genetic evidence of a -associated monogenic microangiopathy. These results show no evidence of association between rare variants of and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the 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.