Cerebral small-vessel disease (SVD) is a well-known cause of stroke, dementia and death, but its pathogenesis is not yet
completely understood. The spectrum of neuroradiological manifestations associated with SVD is wide and may result from chronic and
diffuse or acute and focal ischemia (leukoaraiosis and lacunar infarction) as well as from small-vessel rupture (cerebral microbleeds and
intracerebral hemorrhage). Several lines of evidence from family and twin studies support the hypothesis that genetic factors may
contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge of SVD
pathogenesis and help to identify new therapeutic targets to reduce the burden of SVD-related cognitive decline and stroke disability. A
number of monogenic conditions presenting with clinical features of SVD have been described. Although monogenic disorders account
for only a small proportion of SVD, study of these diseases may provide further insight into the pathogenesis of SVD. In most cases,
however, SVD is thought to be a multifactorial disorder. Several genetic association studies, conducted using the candidate gene and,
more recently, the genome-wide approach, have so far failed to demonstrate a convincing association between SVD and genetic variants.
Methodological issues, particularly related to inaccurate or heterogeneous phenotyping and insufficient sample sizes, have been invoked
as possible reasons for this. Large collaborative efforts and robust replication, as well as implementation of new genetic approaches, are
necessary to identify genetic susceptibility factors for complex SVD.
Keywords: Genetics, hemorrhage, lacunar, monogenic disorders, polygenic, small-vessel disease, white matter lesions, CADASIL,
fabry disease, CARASIL, HEARNS, COL4A, H-CAA.
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