High-resolution molecular karyotyping in patients with developmental delay and/or multiple congenital anomalies in a clinical setting

Authors

  • J Wincent,

    Corresponding author
    1. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, CMM L8:02, Karolinska Institutet, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
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  • B-M Anderlid,

    1. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, CMM L8:02, Karolinska Institutet, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
    2. Department of Clinical Genetics, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
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  • M Lagerberg,

    1. Department of Clinical Genetics, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
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  • M Nordenskjöld,

    1. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, CMM L8:02, Karolinska Institutet, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
    2. Department of Clinical Genetics, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
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  • J Schoumans

    1. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, CMM L8:02, Karolinska Institutet, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
    2. Department of Clinical Genetics, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
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Josephine Wincent, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, CMM L8:02, Karolinska Institutet, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden.
Tel.: +46 8 5177 2521;
fax: +46 8 5177 3620;
e-mail: Josephine.Wincent@ki.se

Abstract

Wincent J, Anderlid B-M, Lagerberg M, Nordenskjöld M, Schoumans J. High-resolution molecular karyotyping in patients with developmental delay and/or multiple congenital anomalies in a clinical setting.

Microarray-based comparative genomic hybridization (array-CGH) enables genomewide investigation of copy-number changes at high resolution and has recently been implemented as a clinical diagnostic tool. In this study we evaluate the usefulness of high-resolution arrays as a diagnostic tool in our laboratory and investigate the diagnostic yield in the first 160 patients who were clinically referred for investigation of developmental delay (DD)/multiple congenital anomalies (MCA). During this period both 38K BAC-arrays and 244K oligonucleotide-arrays were used. Copy-number variations (CNVs) not previously reported as normal variants were detected in 22.5% of cases. In 13.1% the aberrations were considered causal to the phenotype and in 9.4% the clinical significance was uncertain. There was no difference in diagnostic yield between patients with mild, moderate or severe DD. Although the effective resolution of the 244K oligonucleotide-arrays was higher than the 38K BAC-array, the diagnostic yield of both platforms was approximately equal and no causal aberrations <300 kb were detected in this patient cohort. We experienced that increasing the resolution of a whole genome screen in the diagnostic setting has its drawback of detecting an increased number of CNVs with uncertain contribution to a phenotype. Based on our experiences, array-CGH is recommended as the first-step analysis in the genetic evaluation of patients with DD and/or MCA.

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