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High resolution chromosomal microarray in undiagnosed neurological disorders

Authors

  • Katherine B Howell,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Andrew J Kornberg,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • A Simon Harvey,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    3. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
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  • Monique M Ryan,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    3. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
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  • Mark T Mackay,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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  • Jeremy L Freeman,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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  • M Victoria Rodriguez Casero,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Kevin J Collins,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Michael Hayman,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Ahmad Mohamed,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Tyson L Ware,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Damian Clark,

    1. Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Damien L Bruno,

    1. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    2. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
    3. Victorian Clinical Genetic Services, Melbourne, Victoria, Australia
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  • Trent Burgess,

    1. Victorian Clinical Genetic Services, Melbourne, Victoria, Australia
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  • Howard Slater,

    1. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    2. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
    3. Victorian Clinical Genetic Services, Melbourne, Victoria, Australia
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  • George McGillivray,

    1. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
    2. Victorian Clinical Genetic Services, Melbourne, Victoria, Australia
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  • Richard J Leventer

    Corresponding author
    1. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    2. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
    • Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
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  • Conflicts of interest: Dr McGillivray, Dr Slater, Dr Bruno and Mr Burgess were supported by the Victorian Government Operational Infrastructure Support Program. Dr McGillivray, Dr Slater, Dr Bruno and Mr Burgess are employees of Victorian Clinical Genetic Services that owns VCGS Pathology. The other authors report no disclosures.

Correspondence: Dr Richard J Leventer, Department of Neurology, Royal Children's Hospital Melbourne, Flemington Rd, Parkville, Vic. 3052, Australia. Fax: +61 3 9345 5977; email: richard.leventer@rch.org.au

Abstract

Aim

Despite advances in medical investigation, many children with neurological conditions remain without a diagnosis, although a genetic aetiology is often suspected. Chromosomal microarray (CMA) screens for copy number variants (CNVs) and long continuous stretches of homozygosity (LCSH) and may further enhance diagnostic yield. Although recent studies have identified pathogenic CNVs in intellectual disability, autism and epilepsy, the utility of CMA testing in a broader cohort of children with neurologic disorders has not been reported.

Methods

Two hundred fifteen patients with neurological conditions of unknown aetiology were seen over a 6-month period and were prospectively tested by CMA using high-resolution single nucleotide polymorphism (SNP) microarrays (Illumina HumanCytoSNP-12 v2.1 or Affymetrix 2.7M).

Results

Thirty of 215 (14%) patients tested had an abnormal CMA. Twenty-nine had CNVs (13%) and one (0.5%) a clinically significant stretch of homozygosity. Twenty (9.3%) had a CMA finding considered to be pathogenic or involved in susceptibility to the condition of interest, and 10 (4.7%) had findings of unknown significance. Their phenotypes included infantile spasms and other epilepsies, neuromuscular conditions, ataxia, movement disorders, microcephaly and malformations of cortical development. At least one third of patients did not meet national funding criteria for CMA at the time of presentation.

Conclusions

CMA detected clinically significant abnormalities in a broad range of neurologic phenotypes of unknown aetiology. This test should be considered a first-tier investigation of children with neurologic disorders in whom the initial clinical assessment does not indicate a likely aetiology, especially those with severe epilepsies and neurologically abnormal neonates.

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