Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Axel HILLMER

PROVIDER: E-GEOD-51430 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Detection of chromosomal breakpoints in patients with developmental delay and speech disorders.

Utami Kagistia H KH Hillmer Axel M AM Aksoy Irene I Chew Elaine G Y EG Teo Audrey S M AS Zhang Zhenshui Z Lee Charlie W H CW Chen Pauline J PJ Seng Chan Chee CC Ariyaratne Pramila N PN Rouam Sigrid L SL Soo Lim Seong LS Yousoof Saira S Prokudin Ivan I Peters Gregory G Collins Felicity F Wilson Meredith M Kakakios Alyson A Haddad Georges G Menuet Arnaud A Perche Olivier O Tay Stacey Kiat Hong SK Sung Ken W K KW Ruan Xiaoan X Ruan Yijun Y Liu Edison T ET Briault Sylvain S Jamieson Robyn V RV Davila Sonia S Cacheux Valere V

PloS one 20140306 6

Delineating candidate genes at the chromosomal breakpoint regions in the apparently balanced chromosome rearrangements (ABCR) has been shown to be more effective with the emergence of next-generation sequencing (NGS) technologies. We employed a large-insert (7-11 kb) paired-end tag sequencing technology (DNA-PET) to systematically analyze genome of four patients harbouring cytogenetically defined ABCR with neurodevelopmental symptoms, including developmental delay (DD) and speech disorders. We c ...[more]

PMID: 24603971

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Dataset Information

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

Publications

Detection of chromosomal breakpoints in patients with developmental delay and speech disorders.

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