Personalized genome sequencing coupled with iPSC technology identifies GTDC1 as a gene involved in neurodevelopmental disorders

Aksoy, I., Utami, K.H., Winata, C.L., Hillmer, A.M., Rouam, S.L., Briault, S., Davila, S., Stanton, L.W., Cacheux, V.
Human molecular genetics   26: 367-382 (Journal)
Registered Authors
Winata, Cecilia Lanny
phenotype, nervous system disorder, chromosome rearrangements, stem cells, dna, genes, genome, neurons, technology, zebrafish, stem cells, pluripotent, autism spectrum disorder, genome sequencing, neurodevelopmental disorders, individualized medicine, transluminal attenuation gradient, central nervous system development
MeSH Terms
  • Animals
  • Autism Spectrum Disorder/genetics*
  • Autism Spectrum Disorder/metabolism
  • Autism Spectrum Disorder/pathology
  • Cell Differentiation/genetics
  • Central Nervous System/growth & development
  • Central Nervous System/pathology
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental
  • Genome, Human
  • Glycosyltransferases/biosynthesis
  • Glycosyltransferases/genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Induced Pluripotent Stem Cells/metabolism*
  • Induced Pluripotent Stem Cells/pathology
  • Neural Stem Cells/metabolism*
  • Neural Stem Cells/pathology
  • Neurons/metabolism
  • Neurons/pathology
  • Precision Medicine
  • Zebrafish/genetics
  • Zebrafish/growth & development
28365779 Full text @ Hum. Mol. Genet.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes