Table 1 Summary of focused evidence review of the literature of CMA findings in patients with unexplained DD, ID, MCA, or AD
CMA finding | Genetic event | Clinical importance/counseling issues | Additional diagnostic yield | Additional tests considered |
|---|---|---|---|---|
Normal or negative | Balanced rearrangement (e.g., translocation, inversion, insertion) | A balanced rearrangement may interrupt a gene or disrupt regulation of gene expression; recurrence risk counseling is indicated for offspring of parent with a balanced rearrangement | An estimated additional diagnostic yield of 0.78–1.3% after a negative CMA | G-banded karyotype |
Mosaicism for segmental or whole-chromosome aneuploidy | There is very limited evidence indicating whether the presence of mosaicism missed by CMA is associated with an abnormal phenotype | It is not clear what percent of cases is the result of a mosaic chromosomal abnormality that is not detected by either method | G-banded karyotype, FISH | |
Pathogenic or likely pathogenic nonrecurrent single CNV | Copy-number gains due to insertion (versus tandem duplication) | CMA results may show a copy-number gain that could represent either tandem duplication or an unbalanced insertion. When inherited from parent with balanced insertion, there are implications for recurrence risk counseling | Approximately 2% of deletion and duplications are due to balanced insertion in one of the parents | Karyotype or metaphase FISH on the proband and/or parents (depending on the size of the rearrangement) |
Multiple CNVs (≥2) | Insufficient evidence to determine incidence | Associated with a complex karyotype in 88% of cases in one study | Additional studies may be considered as appropriate on an individual case basis | G-banded karyotype and/or metaphase FISH |
Copy-neutral ROH on a single chromosome | UPD | Accurate diagnosis of UPD is only possible with additional molecular testing; follow-up testing should be considered to confirm UPD whenever ROH involves only one chromosome and raises the clinical suspicion for an imprinting disorder or the phenotype is suggestive of an imprinting syndrome | 63% of cases when (1) large ROH, (2) telomeric, (3) affecting chromosome with known imprinting disorder | Microsatellite markers and/or methylation studies |
Copy-neutral ROH on multiple chromosomes (≥2) | Identity by descent (IBD) | May assist in identifying an autosomal recessive disorder caused by a gene in the homozygous region | Results in diagnosis in up to 7% of cases (in a setting of known parental relatedness/consanguinity | Follow-up sequencing and/or targeted copy-number detection |
