Interpretation of copy number alterations identified through clinical microarray-comparative genomic hybridization

Area of Science:

• Genomics
• Human Genetics
• Clinical Diagnostics

Background:

• Many copy number alterations (CNAs) are currently classified as variants of unknown significance (VUS).
• A lack of comprehensive human genome characterization hinders the definitive classification of CNAs as benign.
• There are no established rules or evidence thresholds for defining a CNA as benign.

Purpose of the Study:

• To highlight the need for extensive human genome characterization.
• To emphasize the ongoing efforts in assembling data for assessing CNA pathogenic impact.
• To underscore the challenges and excitement in clinical human genetics due to genomic uncertainties.

Main Methods:

• Review of current understanding of copy number alterations.
• Analysis of the requirements for classifying CNAs as benign.
• Discussion of the implications for clinical array-comparative genomic hybridization (aCGH) interpretation.

Main Results:

• The current understanding of the human genome is insufficient for definitive CNA classification.
• Information for accurate assessment of CNA pathogenic impact is being gathered.
• Clinical interpretation of aCGH is challenging due to genomic knowledge gaps.

Conclusions:

• Further extensive characterization of the human genome is necessary.
• Development of definitive criteria for benign CNAs is required.
• Despite challenges, the field of clinical human genetics remains dynamic and promising.