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 non-recurrent 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 (i) large ROH, (ii) telomeric (iii) 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