Customized high resolution CGH-array for clinical diagnosis reveals additional genomic imbalances in previous...

Area of Science:

• Molecular Cytogenetics
• Genomics
• Medical Diagnostics

Background:

• Array comparative genomic hybridization (aCGH) is a key tool for diagnosing genomic imbalances and understanding disease pathogenesis.
• Custom whole-genome oligonucleotide arrays enhance diagnostic capabilities.

Purpose of the Study:

• To design and evaluate a custom whole-genome oligonucleotide array (KaryoArray®v3.0) for diagnostic use.
• To assess the array's ability to detect novel genomic rearrangements and identify causal imbalances in patients with developmental disorders.

Main Methods:

• Design and implementation of an 8x60K Agilent-based custom array (KaryoArray®v3.0).
• Validation involved a blind test of 120 samples (63 known imbalances, 57 controls).
• Prospective evaluation of 540 patients with intellectual disabilities, autism spectrum disorder, and multiple congenital anomalies.

Main Results:

• The array detected new and unexpected rearrangements in approximately 17.5% of known pathological cases.
• It identified causal genomic imbalances in about 20% of patients with psychomotor delay and/or intellectual disability.
• Additional genomic imbalances were found to co-exist in patients with known chromosomal abnormalities.

Conclusions:

• The custom aCGH array is a valuable tool for diagnostic evaluation of genomic imbalances.
• Implementation as a first-tier test can reveal co-existing imbalances, aiding in genotype-phenotype correlation.
• aCGH is recommended for individuals with trisomies and deletion/duplication syndromes when the phenotype doesn't fully match the genotype.