Abstract Details

Title A New Look into Genes Involved in Malformations of Cortical Development Reveals a Complex Relationship between Molecular Findings and Phenotype

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S08 - (-)

Poster/Presentation
Number 003

Objective

Background MCDs include a wide range of developmental disorders that are important causes of neurodevelopmental delay and epilepsy. Traditionally, MCDs have been associated to genes that control important developmental steps: such as DCX, LIS1 and FLNA. However, more recently a complex picture emerged including candidates such as the tubulins gene family (TUBA1A, TUBB2B and TUBA8). Interestingly, mutations in these genes were reported in various types of MCDs, with no specific clinical/MRI correlation.

Design/Methods Our cohort is composed of 110 patients with different types of MCDs. All of them have been investigated by high resolution volumetric MRI performed in epilepsy a center. Mutation screening was performed by Sanger sequencing of the entire coding region as well as exon-intron boundaries of the following genes FLNA, LIS1, DCX, TUBA1A, TUBB2B, TUBA8, EMX2. In addition, we are performing SNP-array studies (CytoScanHD) to search for unbalanced structural abnormalities in these patients. We used in silico algorithms to predict the protein effect of any variant identified.

Results To date, a total of 45 variants were identified. Potentially pathogenic variants were identified in FLNA (n=2/45), LIS1 (n=2/45), DCX (n=2/45), TUBB2B (n=1/45) and TUBA8 (n=2/45). Possible neutral variants were also identified (n=36/45).

Conclusions Most of the variants identified are neutral polymorphisms which are present in public databases. Only few patients of our cohort present potentially deleterious mutations in the genes analyzed (n=9/110). Interestingly, all potentially deleterious variants identified in tubulins genes (n=3) were in patients with schizencephaly. Considering the small proportion of potentially deleterious variants identified in this cohort it becomes clear that other strategies should be used in other to expedite the identification of potential deleterious variants in MCDs.

Authors/Disclosures
PRESENTER	No disclosure on file
Laurence Poliquin-Lasnier, MD	Dr. Poliquin-Lasnier has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Marilisa M. Guerreiro, MD (State University of Campinas)	No disclosure on file
Fernando Cendes, MD, PhD, FAAN (Departamento de Neurologia; FCM; UNICAMP)	Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Pharma. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB Biopharma. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for United Medical – Brazil. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zodiac Pharma . Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eurofarma – Brazil . Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsia. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Neurology - Epilepsy. The institution of Dr. Cendes has received research support from São Paulo Research Foundation - FAPESP. The institution of Dr. Cendes has received research support from Conselho Nacional de Desenvolvimento Científico e Tecnológico - Brazil . The institution of Dr. Cendes has received research support from NIH.
Iscia Lopes-Cendes, MD, PhD (University of Campinas - UNICAMP)	No disclosure on file
Laura J. Balcer, MD, MSCE, FAAN (NYU Grossman School of Medicine)	Dr. Balcer has received personal compensation for serving as an employee of North American Neuro-Ophthalmology Society. An immediate family member of Dr. Balcer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Children's Hospital of Philadelphia.

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