SNV/Indel and CNV Analysis in Trio‐WES for Intellectual and Developmental Disabilities: Diagnostic Yield & Cost‐Effectiveness

ABSTRACT 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.