Clinical relevance of small copy-number variants in chromosomal microarray clinical testing

Area of Science:

• Genetics
• Molecular Biology
• Clinical Diagnostics

Background:

• Diagnostic chromosomal microarray (CMA) testing recommendations prioritize array resolution for optimal sensitivity.
• The clinical significance of small, nonrecurrent copy-number variants (CNVs) (<500 kb) remains less established compared to larger variants.

Purpose of the Study:

• To investigate the clinical significance of small, nonrecurrent CNVs (<500 kb) identified through CMA testing.
• To evaluate the diagnostic yield of these smaller variants in patients with neurodevelopmental disorders and/or congenital anomalies.

Main Methods:

• Analysis of 4,417 patients undergoing CMA testing over six years (2009-2014).
• Inclusion of all nonpolymorphic small, nonrecurrent CNVs (<500 kb), excluding benign variants and recurrent microdeletions/duplications.

Main Results:

• 8.67% of patients carried at least one small, nonrecurrent CNV.
• 113 patients (2.56%) had a small pathogenic or likely pathogenic CNV, with 56% involving whole-gene or exonic deletions.
• Variants of uncertain significance (VUS) were identified in 3.98% of patients.

Conclusions:

• Small, nonrecurrent CNVs (<500 kb) possess diagnostic relevance in clinical CMA testing.
• Careful clinical interpretation of these small CNVs is crucial for accurate diagnosis.