Cerebral cavernous malformation (CCM)affects brain microvessels appearing enlarged and tangled. Impairment of endothelial cells causes the increased permeability of the blood-brain barrier often resulting in intracerebral haemorrhage. Other clinical manifestations include seizures, headaches, neurological deficits. Lesions can occur sporadically or be inherited followinggerm-line dominant mutations at the three loci KRIT1, CCM2 and PDCD10. However, a small percentage of patients affected by hereditary CCM result negative at genetic test. Therefore, involvement of other genes in development of CCM is a very strong hypothesis. Here we report results obtained by Whole Exome Sequencing (WES) analysis performed on a woman affected by familial CCMand carrying no germ-line at the three CCM known loci. WES was conducted on DNA purified by peripheral blood. Library for paired-ends sequencing was performed using “SureSelectXT Human All Exon V6” kit (Agilent Genomics) and run on an Illumina HiSeq. Obtained reads were filtered, trimmed and aligned to GRCh37 Human Genome assembly. Variant calling was performed by the Genome Analysis Toolkit. Selected variants were validated by Sanger sequencing. Genotyping of these variants was also performed in both affected and healthy consanguineous parents of the proband in order to formulate their association with the pathological phenotype. Five novel variants were selected and confirmed in genes not yet associated with CCM development. However, data are still preliminary, analysis on the other family members is ongoing. In conclusion we identified five novel genes potentially associated with CCM development whose genetic causes are partially still unclear.
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