Large cryptic genomic rearrangements with apparently normal karyotypes detected by array-CGH

Area of Science:

• Genetics
• Molecular Biology
• Clinical Diagnostics

Background:

• Conventional karyotyping has limitations in detecting chromosomal aberrations >5-10 Mb, missing causes of intellectual disability/developmental delay (ID/DD) and multiple congenital anomalies (MCA).
• Array-Comparative Genomic Hybridization (array-CGH) offers improved diagnostic yield (15-20%) for chromosomal abnormalities.

Purpose of the Study:

• To evaluate the utility of array-CGH in identifying large complex rearrangements (LCRs) overlooked by conventional karyotyping in patients with ID/DD and/or MCA.
• To assess the diagnostic yield and clinical significance of LCRs detected by array-CGH.

Main Methods:

• Array-Comparative Genomic Hybridization (array-CGH) was performed on 700 cases with ID/DD, including prenatal diagnoses.
• Fluorescence In Situ Hybridization (FISH) analysis was used to characterize rearrangements in selected cases.
• Karyotyping and array-CGH were compared for diagnostic accuracy.

Main Results:

• Array-CGH identified LCRs (6-18 Mb) in seven patients with normal karyotypes, including three prenatal cases.
• FISH analysis revealed these LCRs were often translocation derivatives, mimicking normal karyotypes.
• Identified genes within rearrangements were associated with specific phenotypic features in some cases.
• Five LCRs were inherited, and two were de novo.

Conclusions:

• Large complex rearrangements can be missed by conventional karyotyping due to limitations in resolution and band appearance.
• Array-CGH is a valuable first-tier approach for precise chromosomal diagnosis and recurrence risk assessment in ID/DD and MCA.
• Array-CGH is crucial in prenatal testing to prevent false negatives arising from karyotype detection limits.