Genome sequencing identifies major causes of severe intellectual disability. A study sequenced the genomes of 50 patients with severe intellectual disability (ID) and their unaffected parents, revealing 84 de novo SNVs and eight de novo CNVs. These mutations were found to be significantly enriched in genes previously linked to ID. A conclusive genetic diagnosis was reached in 20 patients, with a diagnostic yield of 42% in this cohort. The study also identified a compound heterozygous CNV in a recessive mode, leading to a cumulative diagnostic yield of 62% in an unselected cohort. The results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Whole-genome sequencing (WGS) can reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID. The study highlights the importance of WGS in diagnosing ID, as it can detect mutations that were previously undiagnosed by microarray or exome sequencing. The study also identified several structural variants, including a fusion gene in IQSEC2, which may contribute to the patient's phenotype. Additionally, the study found that mosaic mutations in genes such as PIAS1, HIVEP2, and KANSL2 were present in some patients. The study also examined non-coding mutations and found no evidence of pathogenic non-coding mutations. Overall, the study demonstrates the power of WGS in identifying the genetic causes of severe ID and highlights the importance of further research into the role of non-coding mutations in disease.Genome sequencing identifies major causes of severe intellectual disability. A study sequenced the genomes of 50 patients with severe intellectual disability (ID) and their unaffected parents, revealing 84 de novo SNVs and eight de novo CNVs. These mutations were found to be significantly enriched in genes previously linked to ID. A conclusive genetic diagnosis was reached in 20 patients, with a diagnostic yield of 42% in this cohort. The study also identified a compound heterozygous CNV in a recessive mode, leading to a cumulative diagnostic yield of 62% in an unselected cohort. The results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Whole-genome sequencing (WGS) can reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID. The study highlights the importance of WGS in diagnosing ID, as it can detect mutations that were previously undiagnosed by microarray or exome sequencing. The study also identified several structural variants, including a fusion gene in IQSEC2, which may contribute to the patient's phenotype. Additionally, the study found that mosaic mutations in genes such as PIAS1, HIVEP2, and KANSL2 were present in some patients. The study also examined non-coding mutations and found no evidence of pathogenic non-coding mutations. Overall, the study demonstrates the power of WGS in identifying the genetic causes of severe ID and highlights the importance of further research into the role of non-coding mutations in disease.