Exon-focused targeted oligonucleotide microarray design increases detection of clinically relevant variants across...

Area of Science:

• Genomics
• Clinical Diagnostics
• Human Genetics

Background:

• Chromosomal microarrays are standard for postnatal constitutional genome analysis.
• Current arrays often miss intragenic deletions/duplications, a key disease mechanism.
• High-resolution oligonucleotide arrays targeting single exons offer improved detection.

Purpose of the Study:

• To compare the diagnostic performance of traditional vs. new exon-focused oligo-array CGH designs.
• To evaluate the effectiveness of enhanced exon-level coverage for detecting intragenic aberrations.
• To assess the impact on diagnostic yield in patients with developmental disorders.

Main Methods:

• Retrospective analysis of 27,756 patient samples from UK genomic centres.
• Comparison of two oligo-array CGH designs: traditional (v2) and exon-focused (v3).
• Subset analysis (n=19,675) from labs using both array designs.

Main Results:

• The new exon-focused array (v3) successfully detected intragenic aberrations missed by the v2 array.
• This targeted design demonstrated a significant improvement in diagnostic yield.
• Updated genomic data informed the design of the v3 array for enhanced coverage.

Conclusions:

• High-density, exon-targeted oligo-array CGH is a powerful tool for detecting intragenic deletions and duplications.
• The v3 array design represents a significant advancement over traditional arrays for constitutional genome analysis.
• Improved diagnostic yield is achieved through enhanced detection of pathogenic intragenic variants.