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

Area of Science:

• Genetics and Genomics
• Clinical Diagnostics
• Bioinformatics

Background:

• Intellectual and developmental disabilities (IDD) are complex genetic disorders with significant global impact.
• Traditional whole exome sequencing (WES) primarily detects single nucleotide variants (SNVs) and small insertions/deletions (Indels), often yielding limited diagnostic rates in IDD.
• The genetic heterogeneity of IDD necessitates advanced diagnostic strategies beyond SNV/Indel detection.

Purpose of the Study:

• To evaluate the diagnostic utility of integrating copy number variation (CNV) analysis with SNV/Indel analysis in trio-WES for IDD patients.
• To assess the cost-effectiveness and diagnostic yield of the combined approach compared to conventional methods.

Main Methods:

• Trio-based whole exome sequencing (WES) was performed on 187 patients with IDD across 140 families.
• Integrated analysis of SNVs, Indels, and copy number variations (CNVs) was conducted.
• Variant data was analyzed for diagnostic yield, clinical significance, and cost-effectiveness.

Main Results:

• The integrated SNV/Indel and CNV analysis achieved an overall diagnostic rate of 40.11% (75/187).
• SNV/Indel analysis identified 33.16% (62/187) of diagnoses, while CNV analysis contributed an additional 6.95% (13/187).
• The strategy demonstrated significant cost-effectiveness (ICER of $2546.22/diagnosis) and improved detection speed.

Conclusions:

• Integrating CNV analysis into trio-WES significantly enhances the diagnostic yield for intellectual and developmental disabilities.
• This combined approach provides a robust, cost-effective, and time-saving method for diagnosing IDD, benefiting clinical management and reproductive counseling.
• The study highlights the importance of comprehensive genomic analysis for understanding the genetic basis of IDD.