Monogenic causes of stroke: now and the future

Abstract

Most stroke is multifactorial with multiple polygenic risk factors each conferring small increases in risk interacting with environmental risk factors, but it can also arise from mutations in a single gene. This review covers single-gene disorders which lead to stroke as a major phenotype, with a focus on those which cause cerebral small vessel disease (SVD), an area where there has been significant recent progress with findings that may inform us about the pathogenesis of SVD more broadly. We also discuss the impact that next generation sequencing technology (NGST) is likely to have on clinical practice in this area. The most common form of monogenic SVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, due to the mutations in the NOTCH3 gene. Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV α1 and α2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. These monogenic forms of SVD, with overlapping clinical phenotypes, are beginning to provide insights into how the small arteries in the brain can be damaged and some of the mechanisms identified may also be relevant to more common sporadic SVD. Despite the discovery of these disorders, it is often challenging to clinically and radiologically distinguish between syndromes, while screening multiple genes for causative mutations that can be costly and time-consuming. The rapidly falling cost of NGST may allow quicker diagnosis of these rare causes of SVD, and can also identify previously unknown disease-causing variants.

Clinical Pregenetic Screening for Stroke Monogenic Diseases

“…Another limit is that we only tested patients for 5 monogenic causes of stroke, whereas more recently described causes, such as COL4A1 and CARASIL, have not been included in our screening. 28 Furthermore, there was a relatively low National Institutes of Health Stroke Scale score although this is similar to that in previous studies 29,30 and may partly reflect the lower National Institutes of Health Stroke Scale associated with lacunar strokes in diseases, such as CADASIL.…”

Genetics of vascular dementia – review from the ICVD working group

“…Although the above described single gene disorders are believed to account for a small proportion of cases, their prevalence is probably underestimated; systematic studies on well-defined phenotypes and larger series are needed since these diseases are expected to play a crucial role in our understanding of the pathogenesis of VaD and CSVD [21]. …”

Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease

“…Cerebral small vessel disease (SVD) is a heterogeneous group of disorders affecting small vessels of the brain and is commonly recognized to be the leading cause of vascular cognitive impairment and dementia. While in the great majority of cases cerebral SVD is an age‐related sporadic disorder with multifactorial origin, familial monogenic causes have been identified in the last decades in a minority of patients . The monogenic SVDs, which share overlapping clinical and radiological features among them and with the sporadic form, are generally early onset and transmitted with a dominant inheritance pattern.…”

“…While in the great majority of cases cerebral SVD is an age-related sporadic disorder with multifactorial origin, familial monogenic causes have been identified in the last decades in a minority of patients. 1 The monogenic SVDs, which share overlapping clinical and radiological features among them and with the sporadic form, are generally early onset and transmitted with a dominant inheritance pattern. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), 2 due to NOTCH3 gene mutations, is the most common dominantly inherited SVD, hundreds of subjects having been diagnosed worldwide with a prevalence of about 4/100 000 in European countries.…”