Clinical Pregenetic Screening for Stroke Monogenic Diseases

Abstract

Background and Purpose— Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease Methods— We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. Results— In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. Conclusions— In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.

The role of clinical and neuroimaging features in the diagnosis of CADASIL

“…We confirmed that a family history of stroke and dementia as well as the presence of external capsule lacunes are strongly associated with a diagnosis of CADASIL. [9,11,[23][24][25]. Conversely, we found that the presence of severe WMHs, thalamic lacunes, and temporal lobe WMHs may be less useful.…”

“…We developed a new pre-genetic algorithm to select patients with cerebrovascular diseases in whom there is a yield sufficient to merit testing [10][11]. The application of this clinical algorithm allowed the selection of a patient population highly suspected for CADASIL, which was genetically confirmed in a relatively high proportion of cases (12.5%).…”

“…Although the strength of our study is that the screening strategy was firstly applied in a prospectively collected and well phenotyped series of lacunar stroke or TIA patients, some possible limitations of our work should be highlighted. Firstly, the study was conducted on a relative small sample size and the algorithm has not been validated by systematically performing the genetic tests in a pool of randomly selected stroke cases [11]. Thus, the reliability of our algorithm should be assessed on wider series.…”

“…One (1) point score was attributed to every single item (total sum ranging from 0 to 6), and patients with a > 2 score were included in the study and addressed to genetic analysis. The full study methodology has been previously reported [10][11].…”

A stroke gene panel for whole-exome sequencing

“…Previous panels of genes related to monogenic stroke or subtypes of monogenic stroke have been reported, for example, for all types of stroke, such as for targeted sequencing [15] or for massively parallel sequencing [16], as well as compilations of genes intended to be used for the evaluation of a certain stroke subgroup [17]. Although these previous valuable studies presented many genes associated with monogenic stroke, we could not identify in the literature any comprehensive panel that contains a systematic compilation of currently relevant genes for possible monogenic stroke [18][19][20][21].…”