Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited. Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH JILLIAN NICHOLL 1 ,WENDY WATERS 1 ,JOHN C. MULLEY 2,3,4 ,SHANNA SUWALSKI 1 , SUE BROWN 1 ,YVONNE HULL 1 ,CHRISTOPHER BARNETT 4,5 ,ERIC HAAN 4,5 ,ELIZABETH M. THOMPSON 4,5 , JAN LIEBELT 5 ,LESLEY MCGREGOR 5 ,MICHAEL G. HARBORD 6 ,JOHN ENTWISTLE 6 ,CHRIS MUNT 7 , DIERDRE WHITE 8 ,ANTHONY CHITTI 9 ,DAVID BAULDERSTONE 10 ,DAVID KETTERIDGE 11 , ARRAY REFERRAL CONSORTIUM 12 ,KATHRYN FRIEND 2 ,SHARON M. BAIN 1,3 AND SUI YU 1,2,3,4 1 Cytogenetics, Department of Genetic Medicine, Directorate of Genetics and Molecular Pathology, SA Pathology at Women’s and Children’s Hospital, North Adelaide, 2 Molecular Genetics, Department of Genetic Medicine, Directorate of Genetics and Molecular Pathology, SA Pathology at Women’s and Children’s Hospital, North Adelaide, 3 School of Molecular and Biomedical Sciences, The University of Adelaide, 4 School of Paediatrics and Reproductive Health, The University of Adelaide, 5 South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, 6 Centre for Disability Health, North East Clinic, Modbury Hospital, Adelaide, 7 Ashford Medical Centre, Ashford, Adelaide, 8 Flinders Medical Centre, Bedford Park, 9 Calvary Hospital, North Adelaide, 10 Women’s and Children’s Health Network, North Adelaide, 11 Parks Community Health Service, Angle Park, South Australia, Australia; 12 see Acknowledgements for all members Summary The aim of this study was to determine prospectively the frequency of pathogenic chromosomal microdeletions and microduplications in a large group of referred patients with developmental delay (DD), intellectual disability (ID) or autism spectrum disorders (ASD) within a genetic diagnostic service. First tier testing was applied using a standardised oligo-array comparative genomic hybridization (CGH) platform, replacing conventional cytogenetic testing that would have been used in the past. Copy number variants (CNVs) found to be respon- sible for the clinical condition on the request form could all be subdivided into three groups: well established pathogenic microdeletion/microduplication/aneuploidy syndromes, pre- dicted pathogenic CNVs as interpreted by the laboratory, and recently established pathogenic disease susceptibility CNVs. Totalled from these three groups, with CNVs of un- certain significance excluded, detection rates were: DD (13.0%), ID (15.6%), ASD (2.3%), ASD with DD (8.2%), ASD with ID (12.7%) and unexplained epilepsy with DD, ID and ASD (10.9%). The greater diagnostic sensitivity arising from routine application of array CGH, compared with previously used conventional cytogenetics, outweighs the interpretative issues for the reporting laboratory and referring clinician arising from detection of CNVs of uncertain significance. Precise determination of any previously hidden molecular defect responsible for the patient’s condition is translated to improved genetic counselling. Key words: Array CGH, autism spectrum disorders, CNV, copy number variation, developmental delay, intellectual disability, molecular cytogenetics. Received 14 March, revised 30 October, accepted 30 October 2013 INTRODUCTION Developmental delay (DD), intellectual disability (ID) and autism spectrum disorders (ASD) are often associated with congenital abnormalities and have diverse origins. Array comparative genome hybridisation (CGH) now reveals genetic causes through the detection of pathogenic copy number variants (CNVs) 1–10 previously hidden from the cytogeneticist. Fluorescence in situ hybridisation (FISH), 11 having confirmed CNVs detected by array CGH and excluded insertional translocation, 12 can then be applied to cascade testing. Non-allelic homologous recombination 13,14 accounts for the recurrent CNVs, some of which are incompletely penetrant, with variable expressivity modulated through pleiotropy 15 or genetic or environmental interactions. Deletions and duplications at 1q21.1 16,17 and 16p11.2, 7,8,18–21 deletions at 2q23.1, 22,23 15q11.2, 3,8 15q13.3, 1,24,25 16p13.11, 3 16p12.1, 4 16p11.2-p12.2, 26 17q21.31, 8 and 22q11.2, 27 and duplication at 16p13.1 28 are recurrent CNVs that can have diverse out- comes within and between families. The retrospective research investigations cited above led to diagnostic application. Rebates for diagnostic array CGH for developmental delay, intellectual disability, autism spectrum disorders or two or more congenital abnormalities have been provided by Australia’s publicly funded Medicare health system since May 2010. This has resulted in array CGH, combined with FISH if a CNV is identified, replacing the combination of conventional cytogenetics and subtelomere multiplex ligation-dependent probe amplification (MLPA) for the detection of chromosomal abnormalities in individuals with these disorders. Array CGH was carried out in an accredited diagnostic laboratory environment by professionally certified laboratory staff with study objectives to be addressed from routine patient referrals. We set out to determine for what proportion of prospectively referred cases can the genetic cause be determined by an array CGH platform and to ascertain the range of conditions detected by the introduction of this technology to cytogenetics. Pathology (January 2014) 46(1), pp. 41–45 GENETICS Print ISSN 0031-3025/Online ISSN 1465-3931 # 2013 Royal College of Pathologists of Australasia DOI: 10.1097/PAT.0000000000000043