Table 3.

Recommendations for CMA Testing of Individuals with Unexplained Developmental Delay/Intellectual Disability, Autism Spectrum Disorders, or Multiple Congenital Anomalies

Recommendation for CMA Platform:
1. CMA standards should not be specific to a particular array platform. Arrays based on BAC clones, long oligonucleotides or SNP-detecting shorter oligonucleotides can achieve the recommended coverage and level of resolution.
Recommendations for CMA Coverage and Probe Density:
1. In order to perform the same intended purpose as a karyotype, CMA must have uniform coverage to detect all areas of imbalance at a resolution exceeding that of a karyotype (∼5 Mb). Currently, to detect CNV we recommend a resolution of ≥400 kb throughout the genome as a balance of analytical and clinical sensitivity.
2. For oligonucleotide and SNP arrays, multiple consecutive probes are needed to permit a call to be made, so the array must be designed to include sufficient probe density for each targeted region. Note that SNP arrays may require a greater number of consecutive probes to permit a reliable call to be made.
3. Laboratories that choose to add probes to cover Mendelian disease loci should explicitly state the minimum detectable imbalance and clinical sensitivity of the assay for each disease at each locus and point out the availability of sequence-based technology for detecting mutations that are not detectable by CMA.
Recommendations Related to Balanced Rearrangements, Low-Level Mosaicism, and Positive Family History of Known Chromosomal Abnormalities or Reproductive Loss:
1. CMA can detect many more submicroscopic pathogenic genomic imbalances than the number of balanced rearrangements it would miss. Cytogenetically balanced rearrangements and low-level mosaicism, which would not be detected by CMA, cause only a small proportion of all cases of unexplained DD/ID, ASD, and/or MCA.
2. G-banded karyotyping should be offered to patients with a family history of a balanced chromosomal rearrangement, a history of multiple miscarriages, or certain other conditions, as discussed.
Recommendations for a CMA Database:
1. CMA Database should be “platform neutral” and able to incorporate information based on chromosomal position according to the human genome (hg) build.
2. All raw data should be freely accessible to all qualified researchers who register with dbGaP at NCBI.
3. Curated data should be publicly released on a quarterly basis and made available to major genomics resources and commercial vendors, as well as individuals and clinical laboratories.