Analisi genomica mediante microarray di pazienti con difetti congeniti del cervelletto e del tronco encefalico

Cerebellar Brainstem Congenital Defects (CBCD) affected about 1 in 3000-4000 live births with major consequences in terms of morbidity and mortality, although their real incidence is much higher, since most cases are diagnosed in the second trimester of pregnancy. Clinically CBCD are characterized by extreme phenotypic variability, even if typical signs are ataxia, nistagmus, intellectual disability and other variable multiorgan involvement. With the exception of few autosomal recessive or X-linked conditions, CBCD cases are frequently sporadic suggesting that de novo mutations or genomic rearrangements may represent common pathogenetic mechanisms. The goal of this project was to expand the current knowledge on the molecular basis of CBCD, performing a CNVs analysis of a large cohort of sporadic CBCD patients. A cohort of 84 CBCD patients, not including mendelian form of cerebellar defects, was selected for CNVs study. Eight subjects resulted positive to this analysis (9.5%). Further 10 patients analyzed in Cytogenetic diagnostic lab of Mendel Institute have been revaluated and included in this project, since they showed CNVs overlapping to interesting region and/or were affected by CBCD. Using genomic microarray platforms (SNP-array, Affymetrix; a-CGH, Agilent), we detected different chromosomal regions, that may play a relevant role in the pathogenesis of these defects. In particular, recurrent deletions have been disclosed on the long arm of chromosomes 3, 6 and 10. Our data confirm the crucial role of microarray platforms as a tool to identify pathogenic CNVs in CBCD patients. CBCD confirms to be a disorder characterized by an elevated genetic heterogeneity and with incomplete penetrance, suggesting the involvement of further mechanisms (modifier genes, environmental factors) in cerebellar and brain stem development.