Cytogenomic Evaluation of Children with Congenital Anomalies: Critical Implications for Diagnostic Testing and Genetic Counseling.

Abstract

Identification of submicroscopic chromosomal aberrations, as a cause of structural malformations, is currently performed by MLPA (multiplex ligation-dependent probe amplification) or array CGH (array comparative genomic hybridization) techniques. The aim of this study was the evaluation of diagnostic usefulness of MLPA and array CGH in patients with congenital malformations or abnormalities (at least one major or minor birth defect, including dysmorphism) with or without intellectual disability or developmental delay and the optimization of genetic counseling in the context of the results obtained. The MLPA and array CGH were performed in 91 patients diagnosed with developmental disorders and major or minor congenital anomalies. A total of 49 MLPA tests toward common microdeletion syndromes, 42 MLPA tests for subtelomeric regions of chromosomes, two tests for common aberrations in autism, and five array CGH tests were performed. Eight (9 %) patients were diagnosed with microdeletion MLPA, four (4 %) patients with subtelomeric MLPA, one (1 %) patient with autism MLPA. Further three (3 %) individuals had rearrangements diagnosed by array CGH. Altogether, chromosomal microaberrations were found in 16 patients (17 %). All the MLPA-detected rearrangements were found to be pathogenic, but none detected with array CGH could unequivocally be interpreted as pathogenic. In patients with congenital anomalies, the application of MLPA and array CGH techniques is efficient in detecting syndromic and unique microrearrangements. Consistent pre-MLPA test phenotyping leads to better post-test genetic counseling. Incomplete penetrance and unknown inheritance of detected variants are major issues in clinical interpretation of array CGH data.