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: Kagistia H Utami, Axel M Hillmer, Irene Aksoy, Elaine G Y Chew, Audrey S M Teo, Zhenshui Zhang, Charlie W H Lee, Pauline J Chen, Chan Chee Seng, Pramila N Ariyaratne, Sigrid L Rouam, Lim Seong Soo, Saira Yousoof, Ivan Prokudin, Gregory Peters, Felicity Collins, Meredith Wilson, Alyson Kakakios, Georges Haddad, Arnaud Menuet, Olivier Perche, Stacey Kiat Hong Tay, Ken W K Sung, Xiaoan Ruan, Yijun Ruan, Edison T Liu, Sylvain Briault, Robyn V Jamieson, Sonia Davila, Valere Cacheux
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e90852 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24603971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Base Sequence
• Chromosome Breakpoints
• Chromosome Inversion
• DNA Copy Number Variations
• Developmental Disabilities (genetics)
• Female
• Genetic Association Studies
• High-Throughput Nucleotide Sequencing
• Humans
• Language Development Disorders (genetics)
• Male
• Molecular Sequence Data
• Pedigree
• Sequence Analysis, DNA
• Translocation, Genetic