SNV/Indel and CNV Analysis in Trio-WES for Intellectual and Developmental Disabilities: Diagnostic Yield &...

Intellectual and developmental disabilities (IDD) are clinically and genetically heterogeneous disorders of global concern. While whole exome sequencing (WES) is used to identify single nucleotide variants (SNVs) and small insertions/deletions (Indels) in IDD patients, its detection rate is limited. This study evaluated the value of integrating copy number variation (CNV) analysis into traditional SNV/Indel analysis based on trio-WES. One hundred eighty seven patients with IDD in 140 families from southwest China were incorporated into the study cohort. The overall diagnostic rate was 40.11% (75/187), with 33.16% (62/187) from SNV/Indel analysis and 6.95% (13/187) from CNV analysis. SNV/Indel analysis identified 52 variants in 42 genes, including 30 novel and 22 reported variants; CNV analysis identified 11 CNVs, comprising 1 repeat and 10 deletions, with sizes ranging from 1313 to 55 184 kb. 39.29% (55/140) families benefited from this study for their clinical diagnosis, treatment, and reproduction. Furthermore, our strategy, with an incremental cost-effectiveness ratio (ICER) of $2546.22/diagnosis, had demonstrated significant advantages in terms of cost-effectiveness and detection speed compared to previous methods. In general, by incorporating SNV/Indel and CNV analysis based on trio-WES, a robust, cost-effective, and time-saving approach for diagnosing IDD has been developed.