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Personalized genome sequencing coupled with iPSC technology identifies GTDC1 as a gene involved in Neurodevelopmental Disorders

ABSTRACT: The cellular and molecular mechanisms underlying neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The ability to generate patient-specific induced pluripotent stem cells (iPSCs) now offers a novel strategy for modeling human disease. Recent studies have reported the derivation of iPSCs from patients with neurological disorders. The key challenge remains the demonstration of disease-related phenotypes and the ability to model the disease. Here we report a case study with signs of neurodevelopmental disorders (NDDs) harbouring chromosomal rearrangements that were sequenced using long-insert DNA paired-end tag (DNA-PET) sequencing approach. We identified the disruption of a specific gene, GTDC1. By deriving iPSCs from this patient and differentiating them into neural progenitor cells (NPCs) and neurons we dissected the disease process at the cellular level and observed defects in both NPCs and neuronal cells. We also showed that disruption of GTDC1 expression in wild type human NPCs and neurons showed similar phenotype as patient’s iPSCs. Finally, we utilized a zebrafish model to demonstrate a role for GTDC in development of the central nervous system. Our findings highlight the importance of combining sequencing technolgies with the iPSC technology for NDDs modelling that could be applied for personalized medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87568 | GEO | 2017/02/01

SECONDARY ACCESSION(S): PRJNA345205

REPOSITORIES: GEO

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Genome sequencing coupled with iPSC technology identifies GTDC1 as a novel candidate gene involved in Neurodevelopmental Disorders

Project description:We identified genomic structural alterations of six patients with signs of neurodevelopmental disorder (NDDs) that harbour chromosomal rearrangements using large-insert paired-end tag sequencing (DNA-PET). This technique allowed the refinement of chromosomal breakpoints and lead to the identification of seven disrupted genes (GNAQ, RBFOX3, UNC5D, TMEM47, NCAPG2, GTDC1 and XIAP). For one patient we filtered the entire panel of structural variations (SVs) with his parents and identified a unique SV that disrupted a single gene: GTDC1. We then validated the functional consequences of the chromosomal breakpoint disruption of GTDC1 by using patient-derived iPSCs. By differentiating these cells into neural progenitor cells (NPCs) and neurons, we interrogated the disease process at the cellular level and observed defects in the proliferation and glycosylation status of NPCs and also defects in neuronal maturation and function. We compared these results with GTDC1-deficient wild-type human NPCs and neurons, and observed similar phenotypic features as in the patient-derived cells which confirm that GTDC1 is involved in the patient’s phenotype. We show here that the combination of genomic screening with iPSCs technology provides a mechanistic insight into possible contributory effects of candidate genes implicated in NDDs and for personalized medicine. Structural variations were identified by long insert DNA paired-end tag (DNA-PET) sequencing, a mate-pair sequencing approach.

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