Genetic analysis and reporting from whole-exome sequencing data in 1052 patients with intellectual disability

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Intellectual disability (ID) is a complex neurodevelopmental disorder with diverse genetic causes, making etiological diagnosis challenging.
• Current diagnostic methods often struggle to identify the underlying genetic variants due to clinical heterogeneity and genetic diversity.

Purpose of the Study:

• To evaluate the diagnostic utility of whole-exome sequencing (WES) combined with copy number variation (CNV) analysis in a large cohort of individuals with unexplained ID.
• To analyze the genetic etiology and identify causative variants in intellectual disability.

Main Methods:

• Whole-exome sequencing (WES) was performed on 1052 individuals with unexplained ID.
• Analysis included single nucleotide variants (SNVs), insertions/deletions (InDels), and copy number variations (CNVs).
• Variants were classified as pathogenic or likely pathogenic according to established clinical guidelines.

Main Results:

• A diagnostic yield of 43.54% (458/1052) was achieved, identifying 485 pathogenic or likely pathogenic variants.
• Single nucleotide variants (SNVs) constituted the majority of causative variants (68.7%), with autosomal dominant inheritance being the most prevalent pattern.
• Copy number variation (CNV) analysis identified 152 pathogenic CNVs, increasing the overall diagnostic yield by 14.3% and enabling detection of small CNVs.

Conclusions:

• The combination of WES and CNV analysis significantly enhances the molecular diagnosis of intellectual disability, particularly in cases with unclear etiology.
• This integrated approach provides valuable insights into genotype-phenotype correlations and supports clinical management and genetic counseling.
• WES with CNV analysis is a powerful, economical, and effective tool for the precision diagnosis of ID in diverse populations.