neuroscience-2019-accepted-abstracts

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International Conference on

Health Care and

Health Management

Joint Event

November 04-05, 2019 | Prague, Czech Republic

International Conference on

Neuroscience and

Neurological Disorders

Journal of Neurology and Clinical Neuroscience | Volume 3

Deciphering the molecular basis of neuronal development deficits in the recurrent

genomic disorder

Derek JC Tai

Center for Genomic, USA

eciprocal copy number variant (CNV) of chromosomes

16p11.2 (OMIM 611913), 15q13.3 (OMIM 612001), and

15q11.2-13.3 [Prader-Willi syndrome (PWS), OMIM 176270]

are the highly significant recurrent genomic disorders (RGDs)

associated with intellectual disability and autism spectrum

disorder. The non-allelic homologous recombination (NAHR)-

mediated CNV results from mispairing of the flanking

segmental duplications, which can result in either loss or

gain of the unique genic segment (600 kb in 16p11.2 RGD;

1.5 Mb in 15q13.3 RGD; 5.3 Mb in PWS RGD). However,

the pathogenic mechanism and the functional relevance of

individual genes within RGDs and the combined contributions

of multiple genes are not known. To interrogate the region

against an isogenic background, we developed a novel

CRISPR/Cas9 genome engineering approach to efficiently

generate reciprocal CNV that mimics NAHR. With the

comprehensive cell models and the integrated molecular

and computational approaches, we attempt to uncover

the molecular basis for abnormal neurodevelopment in

these disorders by recapitulating neuropathology of RGD

in derivative neuron models. Our preliminary data and

several recent studies have strongly suggested KCTD13 and

CHRNA7 might be one of the drivers of 16p11.2 and 15q13.3

RGDs respectively. We then defined cellular phenotypes,

transcriptional signatures, and co-expression modules that

are differentially altered by RGDs. Our transcriptome profiling

and analyses showed that genes regulating cytoskeleton

(GO:0005856) and translational initiation (GO:0006413)

were significantly altered in the neurons with 16p11.2 CNV,

and the genes involving axon guidance (GO:0007411) and

Wnt signaling pathway (KEGG:04310) aberrantly expressed

due to 15q13.3 perturbation. The neuron phenotyping

experiments revealed aberrant neurite length, branch

points, and electrophysiological features in the RGD neuron

models. These studies will allow us to gain more insights into

the relationship of gene expression to phenotype and the

pathogenic mechanism underlying the disease.

jctai@mgh.harvard.edu