Developmental Delay & Intellectual Disability Testing

The largest specific etiology of identification of developmental delay and intellectual disability is genetic(1). According to the American Academy of Neurology (AAN), the Child Neurology Society (CNS), the American College of Medical Genetics (ACMG), and the International Collaboration for Clinical Genomics (ISCA/ICCG), a chromosomal microarray analysis (CMA) is considered the first-line genetic test to aid in the diagnostic evaluation of ID when patient history and physical examination do not provide an obvious syndrome diagnosis(2-4).  The CytoScan™ Dx Assay is the first IVD whole-genome diagnostic test to aid in identifying the underlying genetic cause of developmental delay, intellectual disability, congenital anomalies, or dysmorphic features in children.

CytoScan Dx Assay detects chromosomal aberrations across the whole genome

  •  This example illustrates two interstitial duplications: in blue, a 5 Mb duplication in 15q11.2->15q13.1; in red, a 1 Mb hemizygous gain in 16p13.11->16p13.11.
  • Due to the high density of non-polymorphic (copy number) probes and polymorphic (SNP) markers in the array, the copy number changes can be visualized in the Log2 ratio track as well as confirmed in the allelic difference track.
  • These microarray findings, in conjunction with clinical evaluation, led to a diagnosis of 15q11 microduplication syndrome.

CytoScan Dx Assay detects chromosomal aberrations of different sizes

CytoScan Dx Assay can accurately detect numerous chromosomal variations of different types, sizes, and genomic locations. In addition to identifying copy number changes, CytoScan Dx Assay is capable of detecting allelic imbalances and copy number neutral abnormalities such as AOH/LOH that can be associated with uniparental disomy (UPD) or consanguinity, both of which may pose increased risk for autosomal recessive conditions.

  •  This example shows two samples each with a hemizygous loss of 515 kb and 83 kb in cytoband 16p13.3 (indicated by red segments) that included the CREBBP OMIM gene. Both of these patients were diagnosed with Rubinstein-Taybi syndrome (RBS) based on clinical evaluation and CMA findings.
  • Left, a sample with many LOH/AOH regions larger than 3 Mb, which may reflect consanguineous origin. 
  • Right, a clinically diagnosed Angelman syndrome sample with a typical LOH/AOH block, which is often caused by iso- UPD in this syndrome. In this particular case, the LOH/AOH spans the whole q-arm and is 79 Mb long. 
  • Individuals with large blocks of LOH/AOH may be at an increased risk for autosomal recessive conditions.

Key benefits

  • First of-its-kind diagnostic test – IVD and CE marked postnatal blood test to aid in the diagnosis of developmental delay, intellectual disabilities, congenital anomalies, or dysmorphic features.
  • Analyze the patient's entire genome with one test – Accurately detect numerous chromosomal variations of different types, sizes, and genomic locations at higher resolution than karyotyping and more comprehensively than conventional FISH.
  • Designed for today and the future – The design of CytoScan Dx Assay, which includes 2.69 million functional markers across the entire genome, helps ensure that most genes are represented, not only those identified as currently relevant.
Key benefits
  • Dual probe content with high-density SNPs – Containing both CN and SNP probes, CytoScan Dx Assay can elucidate allelic imbalances and identify LOH/AOH that can be associated with uniparental disomy or consanguinity, both of which increase the risk of recessive disorders.
    SNP patterns also provide confirmation of copy number changes.
  • Exceptional performance – High specificity, sensitivity, accuracy, and resolution across the genome.
  • Streamlined data analysis – Affymetrix Chromosome Analysis Suite Dx (ChAS Dx) Software has an intuitive graphical interface for streamlined analysis workflows, ISCN 2013 array nomenclature, and links to databases to support data analysis workflows.
  • Improved diagnostic yield – Due to its higher resolution and whole-genome coverage, CytoScan Dx Assay helps improve diagnostic yield by an incremental 12.5% enabling accurate and more effective diagnosis when compared to G-banded karyotype.

 

First-class customer training and support

Customer training is required to implement CytoScan Dx Assay for both new and existing customers. Different options are available based upon your experience level; please contact an Thermo Fisher Scientific Representative for details.

GeneChip System 3000Dx
 Click to enlarge

The GeneChip™ System (GCS) 3000Dx is the most robust system for clinical research and the only IVD and CE marked microarray system for RNA- and DNA-based clinical tests. This GeneChip instrumentation system combined with innovative assays provides a complete platform for hybridizing, washing, staining, and scanning of microarrays. The CytoScan Dx Assay must be run on GeneChip System 3000Dx.

CytoScan Dx Assay is a qualitative assay intended for the postnatal detection of chromosomal copy number variants (CNV) in genomic DNA (gDNA) obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. CytoScan Dx Assay is indicated for the detection of CNVs associated with developmental delay and/or intellectual disability (DD/ID), congenital anomalies, and/or dysmorphic features. Assay results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice including confirmation by alternative methods, parental evaluation, clinical genetic evaluation, and counseling as appropriate. Interpretation of assay results is intended to be performed only by healthcare professionals board certified in clinical cytogenetics or molecular genetics. The assay is intended to be used on the GeneChip System 3000Dx and analyzed by Chromosome Analysis Suite Dx Software (ChAS Dx Software). This device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations.

WARNING: This device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrtions. Interpretation of assay results is intended to be performed only by healthcare professionals, board certified in clinical cytogenetics or molecular genetics.

  • The smallest CNV regions that ChAS Dx calls are 25 kb and 25 markers for losses, and 50 kb and 50 markers for gains. Performance of the assay has not been assessed below these settings.
  • Mosaic copy number <20% may not be reliably detected and detection sensitivity is affected by the size of the CNV.
  • Loss (absence) of heterozygosity (LOH/AOH) has a filter setting of 3 Mb. Performance of the assay has not been assessed for LOH below this setting for reporting.
  • CytoScan Dx Assay cannot identify balanced chromosomal rearrangements, such as translocations or inversions.
  • The assay is validated for use with peripheral whole blood anticoagulated with heparin or EDTA. It has not been validated for any other specimen type.
  • CytoScan Dx Assay is limited to personnel trained in this assay.
  1. Michelson D. J., et al. Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 77(17):1629-1635 (2011).
  2. Miller D. T., et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics 86(5):749-764 (2010).
  3. Manning M., Hudgins L. Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genetics in Medicine 12(11):742-745 (2010).