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.
High resolution chromosomal microarray in undiagnosed neurological disorders
Article first published online: 3 JUN 2013
© 2013 The Authors. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Journal of Paediatrics and Child Health
Volume 49, Issue 9, pages 716–724, September 2013
How to Cite
Howell, K. B., Kornberg, A. J., Harvey, A. S., Ryan, M. M., Mackay, M. T., Freeman, J. L., Rodriguez Casero, M. V., Collins, K. J., Hayman, M., Mohamed, A., Ware, T. L., Clark, D., Bruno, D. L., Burgess, T., Slater, H., McGillivray, G. and Leventer, R. J. (2013), High resolution chromosomal microarray in undiagnosed neurological disorders. Journal of Paediatrics and Child Health, 49: 716–724. doi: 10.1111/jpc.12256
- Issue published online: 5 SEP 2013
- Article first published online: 3 JUN 2013
- Manuscript Accepted: 3 MAY 2013
- Victorian Government Operational Infrastructure Support Program
- chromosomal microarray;
- copy number variant;
- long continuous stretch homozygosity;
- single nucleotide polymorphism microarray.
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.
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).
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.
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.