Abstracts

Rationale: Malformations of cortical development (MCD) are disorders resulting from defects in the embryogenesis of the cerebral cortex and are one of the most important causes of developmental delay and epilepsy. The main types of MCDs are periventricular nodular heterotopia (PNH), lissencephaly/subcortical band heterotopia spectrum (LIS/SBH) and schizencephaly. Mutations in genes acting in mechanisms ranging from control of cell division to neuronal migration were identified as responsible for several types of MCDs. These advances not only improved our understanding about the mechanisms involved in the development of the cerebral cortex but have also provided relevant information that can be used for better diagnosis and management of patients. In this scenario, the main objective of this study was to access and perform a comprehensive molecular genetics study in a large cohort of patients with MCD.Methods: We have studied a total of 111 patients with MCDs divided in the following groups: 27 with PNH, 33 with LIS/SBH and 51 with schizencephaly. We first searched for sequence variations in candidate genes (FNLA, DCX, LIS1, EMX2, TUBA1A, TUBB2B and TUBA8) using the Sanger sequencing method. Subsequently, we checked for structural variants in FLNA, DCX and LIS1 using Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Finally, we took a genomic approach by using single nucleotide polymorphism (SNP)-array technology to studied copy number variations (CNV) in some patients. All sequence variants found were subsequently verified in a group of 200 control individuals. Results: Our results showed 3 pathogenic sequence variants in FNLA and DCX, as well as 6 pathogenic structural variants detected by MLPA in FLNA, LIS1 and DCX. SNP-array technique detected 17 genomic regions, in 12 patients, containing new CNVs. These CNVs involve a number of potential new candidate genes for MCDs, including: TSNARE, DAAM1, ARX, PLXNA1 and HAUS7. In conclusion, our results show a low frequency of mutations in candidate genes previously associated with MCDs, only 2.7% (n=3/111) of our patients have deleterious sequence variants and 18% (n=6/33) have abnormal structural variants in candidate regions. However, by using a genomic approach to look for CNVs we were able to identify several candidate regions/genes that have the potential to be involved in MCDs (12/40= 30%). Conclusions: Our data show that MCDs are genetic heterogeneous; however, it seems that a significant proportion of patients have structural abnormalities that can be identified by SNP-array technology.