The determination of whether a CNV contributes to an abnormal phenotype depends on many factors, including gene content, previous evidence of pathogenic CNVs in the region, type of CNV (deletion or duplication), inheritance pattern, and frequency in unaffected populations. As such, larger CNVs may be more likely to be classified as pathogenic since they have a higher chance of including a dosage-sensitive gene and/or they include a larger number of genes that cumulatively result in an abnormal phenotype. Our experience, as well as that of other groups,53 has shown that the classification of a previously unreported CNV not associated with known disease genes can vary. To address such discrepancies, we used case-control statistical evidence for 14 selected recurrent CNV regions to objectively determine their significance.
