A novel X-linked disorder with developmental delay and autistic features.
OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. nkaya@kfshrc.edu.sa
Namik
N
Kaya
Dilek
D
Colak
Albandary
A
Albakheet
Mohammad
M
Al-Owain
Nada
N
Abu-Dheim
Banan
B
Al-Younes
Jawaher
J
Al-Zahrani
Nahit M
NM
Mukaddes
Aysin
A
Dervent
Naji
N
Al-Dosari
Ali
A
Al-Odaib
Inci V
IV
Kayaalp
Moeenaladin
M
Al-Sayed
Zuhair
Z
Al-Hassnan
Michael J
MJ
Nester
Mohammad
M
Al-Dosari
Hesham
H
Al-Dhalaan
Aziza
A
Chedrawi
Hulya
H
Gunoz
Bedri
B
Karakas
Nadia
N
Sakati
Fowzan S
FS
Alkuraya
Generaso G
GG
Gascon
Pinar T
PT
Ozand
D059786:Abnormal Karyotype; D000328:Adult; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020440:Gene Duplication; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction