Characterization of the Genetic and Phenotypic Landscape of Patients with CNVs in the Chromosome 22q11.2 Region in a Cohort of South African Patients

Abstract

Copy number variants (CNVs) in the chromosome 22q11.2 region are among the most frequently identified genomic rearrangements. However, their phenotypic variability in African populations remains poorly characterised due to limited access to diagnostics and underrepresentation in genomic research. We retrospectively reviewed 129 sub-Saharan African patients diagnosed with CNVs in the chromosome 22q11.2 region over ten years. Clinical, demographic, and genetic data were collected from fluorescence in situ hybridisation, multiplex ligation-dependent probe amplification, and chromosomal microarray analysis (CMA). CNVs were classified by low copy repeat involvement, and genotype-phenotype correlations were explored. A subset of 11 patients underwent analysis using Face2Gene, an AI-driven next-generation phenotyping tool. Deletions accounted for 71% and duplications 29% of cases. Classic CNVs were observed in 68% of patients and atypical CNVs in 32%. A statistically significant association was found between classic CNVs and congenital heart defects (CHDs). The higher prevalence of CHDs, immunological, endocrinological, and developmental abnormalities mirrored global trends; however, a lower frequency of palatal defects was observed. In total, 181 distinct phenotypic features were documented, highlighting the vast phenotypic spectrum associated with these CNVs. Face2Gene correctly identified all deletions using a gestalt-only approach, but performance decreased with a combined gestalt and feature score approach. This study addresses gaps in genomic data from African populations, while demonstrating the vast phenotypic spectrum of CNVs in the chromosome 22q11.2 region. The introduction of CMA markedly improved diagnostic yield annually. While Face2Gene performed well, further validation in larger,more diverse cohorts is needed for improved clinical implementation.