title: 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 modelling human diseases. 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 a similar phenotype as patient's iPSCs. Finally, we utilized a zebrafish model to demonstrate a role for GTDC1 in the development of the central nervous system. Our findings highlight the importance of combining sequencing technologies with the iPSC technology for NDDs modelling that could be applied for personalized medicine.
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore.|University of Lyon, University Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.
authors.forename: Irene
authors.initials: I
authors.lastname: Aksoy
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore.
authors.forename: Kagistia H
authors.initials: KH
authors.lastname: Utami
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore.|International Institute of Molecular and Cell Biology, Warsaw, Poland.|Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Winata
authors.affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Singapore.
authors.forename: Axel M
authors.initials: AM
authors.lastname: Hillmer
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore.
authors.forename: Sigrid L
authors.initials: SL
authors.lastname: Rouam
authors.affiliation: Service de Génétique INEM UMR7355 CNRS-University, Centre Hospitalier Régional d'Orléans, Orléans, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Briault
authors.affiliation: Human Genetics, Genome Institute of Singapore, 60 Biopolis Street, Singapore, Singapore.
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore.|School of Biological Sciences, Nanyang Technological University, 50 Nanyang Avenue, Singapore.|Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis St, Singapore.
authors.forename: Valere
authors.initials: V
authors.lastname: Cacheux
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002490:Central Nervous System / Q000254:growth & development / Q000473:pathology; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D016695:Glycosyltransferases / Q000096:biosynthesis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D057285:Precision Medicine; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development
chemical_list: C484366:GTDC1 protein, human; D016695:Glycosyltransferases