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

Authors

  • Namik Kaya PhD,

    Corresponding author
    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    • Scientist and Head, Neurogenetics Unit, Genetics Department, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia
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    • N.K. and D.C. contributed equally to this work.

  • Dilek Colak PhD,

    1. Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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    • N.K. and D.C. contributed equally to this work.

  • Albandary Albakheet MSc,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Mohammad Al-Owain MD,

    1. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Nada Abu-Dheim BSc,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Banan Al-Younes MSc,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Jawaher Al-Zahrani MSc,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Nahit M. Mukaddes MD,

    1. Department of Child and Adolescent Psychiatry, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
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  • Aysin Dervent MD,

    1. Department of Child and Adolescent Psychiatry, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
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  • Naji Al-Dosari PhD,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Ali Al-Odaib PhD,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Inci V. Kayaalp MD,

    1. Department of Child and Adolescent Psychiatry, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
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  • Moeenaladin Al-Sayed MD,

    1. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Zuhair Al-Hassnan MD,

    1. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Michael J. Nester PhD,

    1. Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Mohammad Al-Dosari MD,

    1. Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Hesham Al-Dhalaan MD,

    1. Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Aziza Chedrawi MD,

    1. Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Hulya Gunoz MD,

    1. Department of Child and Adolescent Psychiatry, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
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  • Bedri Karakas PhD,

    1. Department of Biomedical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Nadia Sakati MD,

    1. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Fowzan S. Alkuraya MD,

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    2. Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia
    3. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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  • Generaso G. Gascon MD,

    1. Department of Biomedical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    Current affiliation:
    1. Department of Neurosciences, Alpert School of Medicine, Brown University, Providence, RI
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  • Pinar T. Ozand MD, PhD

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
    Current affiliation:
    1. Yildiz Technical University, Besiktas, Istanbul, Turkey
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Abstract

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

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