Next generation sequencing for systematic assessment of genetics of small-vessel disease and lacunar stroke.
BACKGROUND
The pathogenesis of cerebral small-vessel disease (SVD) is still incompletely understood, although evidence from family and twin studies supports the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge on SVD pathogenesis. SVE-LA (Small Vessel and Lacunar) project is a multicenter prospective Lombardia region study aimed at applying innovative genetic technologies and accurate patient phenotyping to discover the genetic basis of SVD.


METHODS
A continuous series of subjects (aged 15-80 years) with a clinically and radiologically defined lacunar stroke referring to the participating Lombardia region stroke centers and an adequate number of age- and sex-matched controls are being included into the study. For each patient, clinical, demographic, instrumental, and familial data are collected applying standardized forms. After informed consent, a DNA sample for genetic analysis from patients and controls has been collected. The next generation sequencing (NGS) technology was applied to systematically screen patients for the most important genetic factors both monogenic and polygenic associated with SVD. The study includes also a centralized quantitative and qualitative analysis of neuroimaging studies.


RESULTS
Between March 2011 and October 2013, 212 lacunar stroke patients and 78 controls have been collected. Mean age of cases was 65.8 ± 11.1 years and 67% were men.


CONCLUSIONS
This is the first study applying systematically NGS technology on a wide series of lacunar stroke patients. A translational approach combining a systematic genetic screening with a detailed phenotyping may facilitate the discovery of genetic basis and improve our knowledge in the pathogenesis of SVD.
Department of Emergency Neurology, IRCCS C. Mondino National Neurological Institute Foundation, Pavia, Italy; Cerebrovascular Unit, IRCCS Foundation Neurological Institute 'C.Besta', Milan, Italy. Electronic address: anna.bersano@gmail.com.
Anna
A
Bersano
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Orsetta
O
Zuffardi
Stroke Unit and Neurology, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy.
Leonardo
L
Pantoni
Bio-Medical Informatics Laboratory of the University of Pavia, Pavia, Italy.
Silvana
S
Quaglini
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Roberto
R
Ciccone
Biotechnology Research Laboratory, Foundation IRCCS, Policlinico San Matteo, Pavia, Italy.
Annalisa
A
Vetro
Stroke Unit, IRCCS C. Mondino National Neurological Institute Foundation, Pavia, Italy.
Alessandra
A
Persico
Stroke Unit, IRCCS C. Mondino National Neurological Institute Foundation, Pavia, Italy.
Maria Federica
MF
Denaro
Cerebrovascular Unit, IRCCS Foundation Neurological Institute 'C.Besta', Milan, Italy.
Giuseppe
G
Micieli
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D059345:Cerebral Small Vessel Diseases / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D012189:Retrospective Studies; D059409:Stroke, Lacunar / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
Genetics; lacunar stroke; monogenic disorders; next generation sequencing; polygenic; small-vessel disease