The study by Gilissen et al. (2014) applied whole-genome sequencing (WGS) to 50 patients with severe intellectual disability (ID) and their unaffected parents to identify genetic causes of the disorder. Despite extensive prescreening, including microarray-based copy number variation (CNV) studies and exome sequencing, no molecular diagnosis was established for all patients. Using WGS, 84 de novo single-nucleotide variations (SNVs) affecting coding regions were identified, with a significant enrichment of loss-of-function mutations and genes previously implicated in ID-related disorders. Additionally, eight de novo CNVs were identified, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. Based on the diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients, resulting in a diagnostic yield of 42% in this cohort. The study suggests that de novo SNVs and CNVs affecting the coding region are major causes of severe ID, highlighting the utility of WGS as a comprehensive genetic test for identifying and characterizing genetic variations in patients with severe ID.The study by Gilissen et al. (2014) applied whole-genome sequencing (WGS) to 50 patients with severe intellectual disability (ID) and their unaffected parents to identify genetic causes of the disorder. Despite extensive prescreening, including microarray-based copy number variation (CNV) studies and exome sequencing, no molecular diagnosis was established for all patients. Using WGS, 84 de novo single-nucleotide variations (SNVs) affecting coding regions were identified, with a significant enrichment of loss-of-function mutations and genes previously implicated in ID-related disorders. Additionally, eight de novo CNVs were identified, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. Based on the diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients, resulting in a diagnostic yield of 42% in this cohort. The study suggests that de novo SNVs and CNVs affecting the coding region are major causes of severe ID, highlighting the utility of WGS as a comprehensive genetic test for identifying and characterizing genetic variations in patients with severe ID.