The clinical utility of enhanced subtelomeric coverage in array CGH

Area of Science:

• Genetics and Genomics
• Cytogenetics
• Molecular Biology

Background:

• Subtelomeric chromosome abnormalities are a significant cause of intellectual disability and congenital anomalies.
• Traditional subtelomeric fluorescence in situ hybridization (FISH) probes have limitations in detecting all telomeric rearrangements.
• Array-based comparative genomic hybridization (array CGH) offers a more comprehensive approach to identifying chromosomal aberrations.

Purpose of the Study:

• To enhance subtelomeric region coverage on microarrays for more precise characterization of telomeric abnormalities.
• To evaluate the efficacy of an expanded array CGH platform in detecting clinically relevant subtelomeric aberrations.
• To assess the resolution and frequency of cytogenetic abnormality detection using targeted microarrays.

Main Methods:

• Developed an array CGH platform by adding 1,120 FISH-mapped BAC clones to cover 41 human subtelomeric regions.
• Selected clone contigs at approximately 0.5 Mb intervals, extending an average of 5.7 Mb centromerically from the most distal unique sequence.
• Analyzed 169 clinically significant subtelomeric abnormalities from nearly 7,000 consecutive patient cases using the enhanced array CGH.

Main Results:

• The expanded telomere coverage enabled precise breakpoint definition in 56% of analyzed chromosome abnormalities.
• Forty-four percent of subtelomeric aberrations extended beyond the enhanced coverage, indicating frequent large-scale rearrangements (>5 Mb).
• Identified 42 interstitial deletions missed by standard subtelomere FISH panels and 6 complex rearrangements.

Conclusions:

• Enhanced array CGH microarrays significantly improve the resolution and detection rate of subtelomeric and interstitial chromosomal abnormalities.
• The findings highlight the prevalence of large subtelomeric aberrations and the need for greater genomic representation in diagnostic arrays.
• Targeted microarrays are crucial for advancing the detection of cytogenetic abnormalities with unprecedented precision and frequency in clinical diagnostics.