N.K. and D.C. contributed equally to this work.
A novel X-linked disorder with developmental delay and autistic features
Article first published online: 28 DEC 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 71, Issue 4, pages 498–508, April 2012
How to Cite
Kaya, N., Colak, D., Albakheet, A., Al-Owain, M., Abu-Dheim, N., Al-Younes, B., Al-Zahrani, J., Mukaddes, N. M., Dervent, A., Al-Dosari, N., Al-Odaib, A., Kayaalp, I. V., Al-Sayed, M., Al-Hassnan, Z., Nester, M. J., Al-Dosari, M., Al-Dhalaan, H., Chedrawi, A., Gunoz, H., Karakas, B., Sakati, N., Alkuraya, F. S., Gascon, G. G. and Ozand, P. T. (2012), A novel X-linked disorder with developmental delay and autistic features. Ann Neurol., 71: 498–508. doi: 10.1002/ana.22673
- Issue published online: 20 APR 2012
- Article first published online: 28 DEC 2011
- Accepted manuscript online: 25 NOV 2011 08:37AM EST
- Manuscript Accepted: 4 NOV 2011
- Manuscript Revised: 4 OCT 2011
- Manuscript Received: 27 AUG 2011
- King Faisal Specialist Hospital and Research Centre
Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa.
We evaluated the affected individuals, all maternally related, using childhood autism rating scale (CARS) and Vineland Adaptive scales, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain, electroencephalography (EEG), electromyography (EMG), muscle biopsy, high-resolution molecular karyotype arrays, Giemsa banding (G-banding) and fluorescent in situ hybridization (FISH) experiments, mitochondrial DNA (mtDNA) sequencing, X-chromosome inactivation study, global gene expression analysis on Epstein-Barr virus (EBV)-transformed lymphoblasts, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR).
We have identified a novel Xq12–q13.3 duplication in an extended family. Clinically normal mothers were completely skewed in favor of the normal chromosome X. Global transcriptional profiling of affected individuals and controls revealed significant alterations of genes and pathways in a pattern consistent with previous microarray studies of autism spectrum disorder patients. Moreover, expression analysis revealed copy number–dependent increased messenger RNA (mRNA) levels in affected patients compared to control individuals. A subset of differentially expressed genes was validated using qRT-PCR.
Xq12–q13.3 duplication is a novel global developmental delay and autism-predisposing chromosomal aberration; pathogenesis of which may be mediated by increased dosage of genes contained in the duplication, including NLGN3, OPHN1, AR, EFNB1, TAF1, GJB1, and MED12. ANN NEUROL 2012