Copy number variation (CNV) identification, interpretation, and database from Brazilian patients

Area of Science:

• Human genetics
• Genomic variation analysis
• Population genetics

Background:

• Copy number variations (CNVs) are key genomic variations, but their pathogenicity interpretation is complicated by population-specific frequencies.
• Existing CNV databases lack representation from admixed populations, hindering accurate genetic diagnostics in diverse groups like Brazilians.

Purpose of the Study:

• To analyze and classify copy number variations (CNVs) in a Brazilian cohort.
• To assess the pathogenicity of CNVs within the Brazilian population, considering its unique genetic admixture.
• To establish a reference for CNV interpretation in clinical genetic screenings for Brazilians.

Main Methods:

• Analysis of 1,504 autosomal CNVs from 268 Brazilian individuals with neurodevelopmental disorders and/or congenital malformations.
• Classification of CNV pathogenicity based on gene content and overlap with known benign/pathogenic variants.
• Comparison of identified CNV frequencies with public databases of structural variants.

Main Results:

• Classified 1,504 autosomal CNVs: 92.9% benign, 1.6% likely benign, 2.6% VUS, 0.2% likely pathogenic, and 2.7% pathogenic.
• Identified recurrent CNVs (e.g., 14q32.33, 22q11.22, 1q21.1, 1p36.32 gains) with increased frequency in the Brazilian sample compared to public databases.
• Considered recurrent CNVs classified as likely benign or VUS as non-pathogenic within this Brazilian cohort.

Conclusions:

• Highlights the critical need for incorporating CNV data from diverse, admixed populations for accurate clinical interpretation.
• Suggests that certain recurrent CNVs, previously unclassified or VUS, may be benign in the Brazilian population.
• Emphasizes the importance of population-specific genomic references for improving diagnostic accuracy in genetic screenings.