This study demonstrates the effectiveness of an unbiased genotype-driven approach in identifying novel genetic causes of severe developmental disorders (DDs). By analyzing 1,133 children with undiagnosed DDs and their parents using exome sequencing and array-based detection of chromosomal rearrangements, the researchers discovered 12 novel genes associated with DDs. These findings increase the diagnostic yield from 28% to 31%. The study highlights the importance of comprehensive, genome-wide and nationwide strategies to elucidate the underlying causes of rare genetic disorders. The authors also observed clustering of missense mutations in six newly implicated genes, suggesting that normal development is perturbed by activating or dominant negative mechanisms. The findings underscore the value of integrating statistical genetics with phenotypic similarity and functional plausibility to identify novel DD genes. Additionally, the study found a significant excess of functional *de novo* mutations in dominant and X-linked DD genes, indicating that these mutations can be sufficient to cause disease. The authors also conducted zebrafish knockdown experiments to assess the developmental role of candidate genes, further supporting the identification of novel DD genes.This study demonstrates the effectiveness of an unbiased genotype-driven approach in identifying novel genetic causes of severe developmental disorders (DDs). By analyzing 1,133 children with undiagnosed DDs and their parents using exome sequencing and array-based detection of chromosomal rearrangements, the researchers discovered 12 novel genes associated with DDs. These findings increase the diagnostic yield from 28% to 31%. The study highlights the importance of comprehensive, genome-wide and nationwide strategies to elucidate the underlying causes of rare genetic disorders. The authors also observed clustering of missense mutations in six newly implicated genes, suggesting that normal development is perturbed by activating or dominant negative mechanisms. The findings underscore the value of integrating statistical genetics with phenotypic similarity and functional plausibility to identify novel DD genes. Additionally, the study found a significant excess of functional *de novo* mutations in dominant and X-linked DD genes, indicating that these mutations can be sufficient to cause disease. The authors also conducted zebrafish knockdown experiments to assess the developmental role of candidate genes, further supporting the identification of novel DD genes.