Abstract Details

Title Uncovering the Neurogenetic Program of 2q37 Syndrome by Integrative Genomics and Cerebral Organoids

Topic General Neurology

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 4-002

Background 2q37 deletion syndrome is a rare syndrome characterized by multiple phenotypic features including bone, cardiovascular alterations, neurodevelopmental including autism and microcephaly. Despite attempts to define genotype-phenotype correlation, the genes responsible for neurological phenotypes are unknown. In the past, we identified a 486kb deletion in a patient with microcephaly and hypoplasia of the corpus callosum pointing to a genomic region in distal 2q37 with multiple CNS genes.

Objective

To perform a deep genomic analysis of the entire 2q37 segment to find genes involved in neuronal dysfunction.

Design/Methods

We use the Allen brain Atlas developmental framework from 8 weeks to 40 years of age. Guilt-by association survey of genomic neighbors by pearson correlation of RNAseq data. We used the Decipher Clinical genome database to correlate the reported genomic alterations of selected genes. We use human cerebral organoids to perform scRNAseq and confocal imaging of immunohistochemistry to examine expression to confirm candidates in cerebral organoids at 70 days in culture.

Results We performed clustering of more than 80 genes that showed four different developmental clusters that correlated with increased expression in the human brain, we found PTMA, KIF1A and SEPT2 showing high expression in all data sets and in a variety of neuronal cell types from interneurons to neuroepithelial cells using scRNAseq. Organoid staining with IHC showed that PTMA and SEPT2 had high expression in cortical progenitors The expression pattern in the cortex shows that many of the highly expressed genes in 2q37are expressed in inhibitory neurons and may explain the hyperexcitability seen in 2q37 patients. We found an increased number of single nucleotide variants in KIF1A associated with multiple neurological phenotypes

Conclusions

The results showed that KIF1A, SEPT2 and PTMA are genes with high confidence to play a distinct function in brain development and 2q37 deletion syndrome.

Authors/Disclosures
Jaime Imitola, MD, FAAN (UConn Health MS center) PRESENTER	Dr. Imitola has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis . The institution of Dr. Imitola has received research support from biogen. Dr. Imitola has a non-compensated relationship as a Board Member with National MS Society that is relevant to AAN interests or activities. Dr. Imitola has a non-compensated relationship as a Committee Member with International Society for Stem Cell Research that is relevant to AAN interests or activities.
Joshua C. Fedorko	Mr. Fedorko has nothing to disclose.
Fumihiro Watanabe (UCONN Health)	No disclosure on file