Trio exome sequencing in patients with global developmental delay and intellectual disability in Rwanda

Abstract

Intellectual disability (ID) and global developmental delay (GDD) are clinically and genetically heterogeneous conditions characterized by impairments in cognitive, motor, and behavioral functions. Despite advances in genomic medicine, individuals of African ancestry remain significantly underrepresented in global genomic databases, limiting variant interpretation and equitable access to precision diagnostics. Data on the genetic etiology of ID/GDD in sub-Saharan Africa, particularly in Rwanda, remain limited. This study aimed to investigate the genetic basis of GDD/ID using trio exome sequencing (trio ES). We analyzed 25 families, including 23 trios and 1 quad, comprising 25 children with syndromic GDD/ID recruited from a hospital setting. Detailed clinical, demographic, and phenotypic data were collected. Trio ES was performed to detect single-nucleotide variants (SNVs), small insertions/deletions (indels), and copy number variants (CNVs). Trio ES achieved a diagnostic yield of 60% (15/25 families), identifying 13 pathogenic and 3 likely pathogenic variants. These included 8 CNVs (50%) and 8 SNVs (50%), with most variants occurring de novo in genes associated with neurodevelopmental disorders. The combination of comprehensive clinical evaluation and trio ES demonstrated a high diagnostic yield in this clinically selected hospital-based Rwandan cohort. These findings support the integration of genomic testing into routine clinical practice to improve timely diagnosis and patient management. This study expands the phenotypic and molecular spectrum of GDD/ID in sub-Saharan Africa and contributes to improving genomic data from underrepresented African populations. However, these findings are based on a highly selected clinically selected cohort and require validation in larger population-based studies.