+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Human Molecular Genetics 26(2): 367-382

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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 060084383

Download citation: RISBibTeXText

PMID: 28365779

DOI: 10.1093/hmg/ddw393

Related references

Exome and genome sequencing of neonates with neurodevelopmental disorders. Future Neurology 7(6): 655-658, 2012

Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus. Plos Genetics 12(5): E1006000-E1006000, 2016

Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Science Translational Medicine 6(265): 265ra168-265ra168, 2015

Annual research review: The (epi)genetics of neurodevelopmental disorders in the era of whole-genome sequencing--unveiling the dark matter. Journal of Child Psychology and Psychiatry, and Allied Disciplines 56(3): 278-295, 2015

Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation. Mutagenesis 29(5): 341-350, 2015

Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene. Journal of Neurodevelopmental Disorders 5(1): 15-15, 2013

Re: whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. European Urology 67(2): 350-351, 2015

Deep sequencing of Brachypodium small RNAs at the global genome level identifies microRNAs involved in cold stress response. Bmc Genomics 10: 449-449, 2009

Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene. Molecular Genetics and Metabolism 119(3): 214-222, 2016

Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene Disorders. Cold Spring Harbor Perspectives in Medicine 6(2): A023168-A023168, 2016

Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. Journal of Pathology 238(4): 543-549, 2016

Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. Plos Genetics 6(6): E1000991-E1000991, 2010

Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma. Journal of Infectious Diseases 211(11): 1842-1851, 2015

Genome-scale sequencing to identify genes involved in Mendelian disorders. Current Protocols in Human Genetics 79: Unit 6.13.-Unit 6.13., 2014

Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders. Journal of Visualized Experiments 122), 2017