title: Detection of chromosomal breakpoints in patients with developmental delay and speech disorders.
abstract: 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 characterized structural variants (SVs) specific to each individual, including those matching the chromosomal breakpoints. Refinement of these regions by Sanger sequencing resulted in the identification of five disrupted genes in three individuals: guanine nucleotide binding protein, q polypeptide (GNAQ), RNA-binding protein, fox-1 homolog (RBFOX3), unc-5 homolog D (C.elegans) (UNC5D), transmembrane protein 47 (TMEM47), and X-linked inhibitor of apoptosis (XIAP). Among them, XIAP is the causative gene for the immunodeficiency phenotype seen in the patient. The remaining genes displayed specific expression in the fetal brain and have known biologically relevant functions in brain development, suggesting putative candidate genes for neurodevelopmental phenotypes. This study demonstrates the application of NGS technologies in mapping individual gene disruptions in ABCR as a resource for deciphering candidate genes in human neurodevelopmental disorders (NDDs).
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Kagistia H
authors.initials: KH
authors.lastname: Utami
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Axel M
authors.initials: AM
authors.lastname: Hillmer
authors.affiliation: Stem Cells and Developmental Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Irene
authors.initials: I
authors.lastname: Aksoy
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Elaine G Y
authors.initials: EG
authors.lastname: Chew
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Audrey S M
authors.initials: AS
authors.lastname: Teo
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Zhenshui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Computational and Mathematical Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Charlie W H
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Computational and Mathematical Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Scientific & Research Computing, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Chan Chee
authors.initials: CC
authors.lastname: Seng
authors.affiliation: Computational and Mathematical Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Pramila N
authors.initials: PN
authors.lastname: Ariyaratne
authors.affiliation: Computational and Mathematical Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Sigrid L
authors.initials: SL
authors.lastname: Rouam
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Lim Seong
authors.initials: LS
authors.lastname: Soo
authors.affiliation: Eye and Developmental Genetics Research, The Children's Hospital at Westmead, Children's Medical Research Institute and Save Sight Institute, Sydney, New South Wales, Australia; Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Saira
authors.initials: S
authors.lastname: Yousoof
authors.affiliation: Eye and Developmental Genetics Research, The Children's Hospital at Westmead, Children's Medical Research Institute and Save Sight Institute, Sydney, New South Wales, Australia; Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Prokudin
authors.affiliation: Department of Cytogenetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Gregory
authors.initials: G
authors.lastname: Peters
authors.affiliation: Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Felicity
authors.initials: F
authors.lastname: Collins
authors.affiliation: Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Meredith
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Department of Immunology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Alyson
authors.initials: A
authors.lastname: Kakakios
authors.affiliation: Unité de Génétique, Centre Hospitalier, Blois, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Haddad
authors.affiliation: Service de Genetique INEM UMR7355 CNRS-University, Centre Hospitalier Régional d'Orléans, Orléans, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Menuet
authors.affiliation: Service de Genetique INEM UMR7355 CNRS-University, Centre Hospitalier Régional d'Orléans, Orléans, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Perche
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Stacey Kiat Hong
authors.initials: SK
authors.lastname: Tay
authors.affiliation: Computational and Mathematical Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Ken W K
authors.initials: KW
authors.lastname: Sung
authors.affiliation: Genome Technology and Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Genome Technology and Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.affiliation: Service de Genetique INEM UMR7355 CNRS-University, Centre Hospitalier Régional d'Orléans, Orléans, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Briault
authors.affiliation: Eye and Developmental Genetics Research, The Children's Hospital at Westmead, Children's Medical Research Institute and Save Sight Institute, Sydney, New South Wales, Australia.
authors.forename: Robyn V
authors.initials: RV
authors.lastname: Jamieson
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Valere
authors.initials: V
authors.lastname: Cacheux
mesh_terms: D001483:Base Sequence; D056905:Chromosome Breakpoints; D007446:Chromosome Inversion; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic