Additional Information

Method:

Chromosomal microarray (CMA) of genomic DNA uses the Illumina Infinium Global Diversity Array with Cytogenetics-8 v1.0 BeadChip. This BeadChip includes 1.8 million probes regularly spaced throughout the genome with higher density across exons of clinically relevant genes. The copy number results are analyzed using the BioDiscovery NxClinical v6.2 software with Human Genome build 19 (GRCh37/hg19 Feb 2009) as a reference. Lesions are interpreted in accordance with the ACMG standards and guidelines. Cytogenomic nomenclature is reported per ISCN 2020 guidelines.

Detection is limited to copy number losses of at least 6 kb in size containing a minimum of 15 consecutive probes and copy number gains greater than 50 kb containing a minimum of 40 consecutive probes. Mosaicism greater than 20% is generally detected by this CMA. Within this limit of detection, all pathogenic or likely pathogenic copy number variants will be reported, including incidental findings not associated with the indication for testing, following the ACMG recommendations. Variants of uncertain significance (VUS) may be included when the region contains protein-coding genes with a known or suspected disease association. Copy neutral Regions of Homozygosity (ROH) are reported when the pattern and size is suggestive of complete or partial uniparental disomy on a chromosome known to have UPD of clinical significance. Genome-wide ROH segments that total 2% or more of the autosomal complement will be reported. Additionally, a single ROH may be reported when it raises the possibility of a recessive disorder with a causative gene located in the region.

Additional studies may be performed to further characterize anomalies detected by CMA including chromosome analysis on 68-70 hour culture with mitogens, fluorescence in situ hybridization (FISH), or ddPCR copy number analysis. When cord blood and an accompanying maternal specimen are provided, short tandem repeat (STR) analysis is performed to assess for the presence of maternal cell contamination. These supplemental studies will be manually scored.

Limitations:

On its own, CMA does not provide information about the structural nature of a finding. CMA will not detect balanced alterations (reciprocal translocations, Robertsonian translocations, inversions, or balanced insertions). CMA will not detect methylation, point mutations, or small insertions/deletions (indels) below the resolution of this assay as described above. Additionally, it may not detect low-level mosaicism, tetraploidy, or marker chromosomes that only contain heterochromatin.  Given these limitations, if a genetic cause is still suspected, additional testing may be warranted. The results are not intended to be used as the sole means for clinical diagnosis or patient management decisions.

References:

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