Test code: 16478

Clinical use

• Determine the genetic etiology of developmental delay, intellectual disability, autism spectrum disorders (ASDs), congenital anomalies, or dysmorphic features
• Confirm or exclude the diagnosis of known chromosomal syndromes
• Further define ambiguities arising from cytogenetic or FISH studies
• Assist in clinical management and genetic counseling

Clinical background

Global developmental delay, intellectual disability, ASDs, congenital anomalies, and dysmorphic features may be caused by environmental factors, genetic factors, or a combination of both. Determining the cause is important for long-term patient management and genetic counseling. Chromosomal abnormalities such as copy-number variants (CNVs) are known to cause developmental delay and intellectual disability.1 CNVs are also estimated to occur in 8% to 21% of patients with ASDs.2 Chromosomal microarray analysis (CMA) is a powerful method of identifying CNVs, many of which are associated with clinically actionable conditions.3

The American College of Medical Genetics (ACMG) recommends CMA as a first-line genetic test for developmental delay, intellectual disability, ASDs, and multiple congenital anomalies.2,4 This recommendation is based, in part, on a literature review that included over 21,000 patients with developmental delay/intellectual disability, ASDs, or multiple congenital anomalies.5 The diagnostic yield was 15% to 20% for CMA testing versus ~3% for G-banded karyotyping and ~6% for subtelomeric fluorescence in situ hybridization (FISH) in combination with G-banded karyotyping.5 In individuals with complex ASDs, CMA testing can result in a diagnostic yield of over 25%.2 ACMG still considers karyotyping a first-line test when patients are suspected of having a recognizable chromosomal syndrome such as trisomy 21 or 18, Turner syndrome, or Klinefelter syndrome.2,4

The ACMG further recommends testing of family members under certain clinical situations.6 For example, testing the parent of an affected child can help determine whether a CNV is inherited or de novo.6 In addition, CNVs of uncertain significance may be clinically significant if found in a parent of an affected patient with similar clinical features.5,6 However, identifying CNV pathogenicity, or lack thereof, based on inheritance is a minor contributor using the current points-based interpretation scoring system (see https://cnvcalc.clinicalgenome.org/redmine/projects/cnvcalc/cnv_calculator/selector), especially if the phenotypes are nonspecific (those that are more common in the general population, eg, intellectual disability).7

The oligonucleotide-single nucleotide polymorphism (oligo-SNP) array contains over 2.67 million probes and covers regions of known CNVs. It can confirm the diagnosis of suspected disorders associated with known chromosomal syndromes and is especially well suited for determining the genetic cause of less well-described disorders. The oligo-SNP format provides extensive information across the genome, allowing precise definition of breakpoints and detection of uniparental disomy, copy number–neutral regions of homozygosity (ROH), and, in some cases, consanguinity.

Interpretive information

The presence of specific chromosomal alterations previously associated with developmental delay, intellectual disability, ASDs, multiple congenital anomalies, or dysmorphic features suggests that these findings are most likely the cause of the respective disorder. CNVs of uncertain significance (equivocal findings) may be followed up with parental testing to help distinguish pathogenic from benign results, especially when clinical features are well defined and specific.7 A CNV is more likely to be pathogenic if the same CNV is detected in an affected parent; conversely, a CNV is more likely to be benign if it is detected in an unaffected parent.5,6

Although the array provides extensive information across the genome, normal results do not rule out the possibility of chromosomal abnormalities. This assay will not detect rearrangements that do not result in a gain or loss of genetic material (eg, balanced reciprocal translocations or inversions) or aberrations smaller than the resolution of the array. The performance of this test for detection of mosaicism has not been established; lower-level mosaicism may not be detected. The array effectively genotypes SNPs across the genome, but it will not detect sequence variants or other alterations at the single-gene level for the purposes of carrier screening or detection of single-gene disorders.

Additional assistance in interpretation of results is available from our Genomic Science Specialists by calling Genomic Client Services at 1.866.GENE.INFO (1.866.436.3463).