In an important subset of CMA cases, the potential functional significance of a particular CNV may be unknown and is referred to as a variant of uncertain clinical significance (VOUS). Parental and family studies can be helpful in the clinical interpretation of these cases, as a de novo occurrence of the CNV strengthens the evidence that it is pathogenic. However, the significance of many CNVs still remains uncertain even after familial studies due to variable expressivity or incomplete penetrance. Therefore, it would be extremely beneficial to improve our knowledge of the functional significance of CNVs throughout the genome by performing comparative analyses of large datasets from case cohorts and control populations to definitively associate specific genomic regions with human disease.
