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A novel X‐linked disorder with developmental delay and autistic features
Author(s) -
Kaya Namik,
Colak Dilek,
Albakheet Albandary,
AlOwain Mohammad,
AbuDheim Nada,
AlYounes Banan,
AlZahrani Jawaher,
Mukaddes Nahit M.,
Dervent Aysin,
AlDosari Naji,
AlOdaib Ali,
Kayaalp Inci V.,
AlSayed Moeenaladin,
AlHassnan Zuhair,
Nester Michael J.,
AlDosari Mohammad,
AlDhalaan Hesham,
Chedrawi Aziza,
Gunoz Hulya,
Karakas Bedri,
Sakati Nadia,
Alkuraya Fowzan S.,
Gascon Generaso G.,
Ozand Pinar T.
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22673
Subject(s) - gene duplication , global developmental delay , autism , genetics , biology , copy number variation , autism spectrum disorder , comparative genomic hybridization , microarray , heritability of autism , gene , phenotype , gene expression , chromosome , medicine , psychiatry , genome
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. Interpretation: 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