Array CGH in children and adolescents with developmental delay or intellectual disability: are there phenotypic clues to clinically relevant chromosomal microaberrations?

Aims: Array comparative genomic hybridization (CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Although array CGH offers a high diagnostic yield, the majority of patients tested do not show any copy number variations (CNV). Our study aimed at both, enlarging the phenotype of chromosomal microaberrations and delineating clinical criteria, which may help separating patients with from those without CNV.

Methods: We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. We compared these data with previously reported microaberrations and compared the phenotypic features of patients with clinical significant CNV with those of patients without any CNV.

Results: Array CGH detected CNVs in 21% (72/342) of patients. Approximately two thirds (45/72) of CNVs represented well-known microaberration syndromes and unbalanced translocations, corresponding to an overall diagnostic yield of 13% (45/342). Most of the remaining CNVs were previously unreported and of uncertain clinical significance. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with chromosomal microaberrations compared to children with normal array CGH results.

Conclusion: In patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any congenital anomaly, especially a congenital heart defect, or a disturbance of somatic growth, including primary microcephaly, acquired short stature, or poor weight gain, is part of the patient's phenotype.

Developmental delay - intellectual disability - array CGH - CNV - chromosomal microaberrations - microdeletion and microduplication syndromes