Clinical exome sequencing (CES) was performed on 814 patients with undiagnosed genetic conditions at UCLA between 2012 and 2014. The study compared trio-CES (sequencing of parents and affected child) and proband-CES (sequencing of the affected individual only) to assess diagnostic yield. Trio-CES had a higher molecular diagnosis rate (31%) compared to proband-CES (22%). For children with developmental delay, trio-CES achieved a 41% diagnosis rate, while proband-CES had only 9%. Trio-CES was more effective in detecting de novo and compound heterozygous variants. The overall diagnosis rate was 26%, with 213 out of 814 cases diagnosed. The study found that CES was particularly effective in identifying genetic causes of developmental delay, retinal disorders, and other conditions. However, it was less effective for ataxia and disorders of sexual development. The study also noted that CES could identify novel disease-causing genes, such as KCNT1 and TUBB2A. While CES is not designed to detect copy number variants or mitochondrial genome variants, it can identify large deletions or duplications in some cases. The study also addressed incidental findings, noting that 5% of cases had likely pathogenic variants in genes like BRCA1 and BRCA2. The study concluded that trio-CES is more effective than proband-CES for diagnosing genetic conditions, especially in genetically heterogeneous disorders like developmental delay. However, the study had limitations, including potential biases in referrals and the inability to detect all types of mutations. The study highlights the importance of CES in diagnosing rare genetic disorders and the need for further research to validate its effectiveness and impact on clinical and economic outcomes.Clinical exome sequencing (CES) was performed on 814 patients with undiagnosed genetic conditions at UCLA between 2012 and 2014. The study compared trio-CES (sequencing of parents and affected child) and proband-CES (sequencing of the affected individual only) to assess diagnostic yield. Trio-CES had a higher molecular diagnosis rate (31%) compared to proband-CES (22%). For children with developmental delay, trio-CES achieved a 41% diagnosis rate, while proband-CES had only 9%. Trio-CES was more effective in detecting de novo and compound heterozygous variants. The overall diagnosis rate was 26%, with 213 out of 814 cases diagnosed. The study found that CES was particularly effective in identifying genetic causes of developmental delay, retinal disorders, and other conditions. However, it was less effective for ataxia and disorders of sexual development. The study also noted that CES could identify novel disease-causing genes, such as KCNT1 and TUBB2A. While CES is not designed to detect copy number variants or mitochondrial genome variants, it can identify large deletions or duplications in some cases. The study also addressed incidental findings, noting that 5% of cases had likely pathogenic variants in genes like BRCA1 and BRCA2. The study concluded that trio-CES is more effective than proband-CES for diagnosing genetic conditions, especially in genetically heterogeneous disorders like developmental delay. However, the study had limitations, including potential biases in referrals and the inability to detect all types of mutations. The study highlights the importance of CES in diagnosing rare genetic disorders and the need for further research to validate its effectiveness and impact on clinical and economic outcomes.