The Deciphering Developmental Disorders (DDD) study identified 94 genes enriched for damaging de novo mutations (DNMs) in individuals with severe, undiagnosed developmental disorders (DDs). These genes include 14 previously without compelling evidence. The study sequenced exomes of 4,293 families and meta-analyzed data from 3,287 individuals, revealing that 42% of the cohort carry pathogenic DNMs, with approximately half disrupting gene function. The average birth prevalence of DDs caused by DNMs is estimated at 1 in 213 to 1 in 448, depending on parental age, equating to nearly 400,000 children born annually. Key factors influencing diagnostic yield include the sex of the affected individual, parental relatedness, and parental age. The study found that males are less likely to carry pathogenic DNMs, and individuals with affected family members are less likely to have pathogenic DNMs. Paternal age was weakly associated with pathogenic DNMs, but a strong paternal age effect was confirmed when analyzing all DNMs. The study identified 93 genes with genome-wide significance, including 80 with prior evidence of DD association. It also discovered 14 new genes with no prior evidence of DD causation. The study highlights the importance of considering de novo causation in all families. The prevalence of pathogenic missense and truncating DNMs was estimated at 41.8% of the cohort. The study also found that 59% of excess missense and truncating DNMs operate by loss-of-function mechanisms, while 41% by altered-function. The study estimated the birth prevalence of monoallelic developmental disorders at 1 in 295, highlighting the cumulative population morbidity and mortality of these disorders. The study emphasizes the need for larger studies and novel analytical strategies to discover remaining dominant developmental disorders. The integration of accurate phenotypic data improves the power to identify ultrarare DDs with distinctive clinical presentations. The study provides visual summaries of phenotypes associated with each gene and anonymized average face images for genome-wide significant genes. The study also highlights the importance of considering both loss-of-function and altered-function mechanisms in DDs. The findings underscore the role of de novo mutations in the genetic architecture of severe developmental disorders, with approximately half of these disorders attributed to loss-of-function and altered-function mechanisms. The study provides a comprehensive understanding of the prevalence, architecture, and mechanisms of de novo mutations in developmental disorders.The Deciphering Developmental Disorders (DDD) study identified 94 genes enriched for damaging de novo mutations (DNMs) in individuals with severe, undiagnosed developmental disorders (DDs). These genes include 14 previously without compelling evidence. The study sequenced exomes of 4,293 families and meta-analyzed data from 3,287 individuals, revealing that 42% of the cohort carry pathogenic DNMs, with approximately half disrupting gene function. The average birth prevalence of DDs caused by DNMs is estimated at 1 in 213 to 1 in 448, depending on parental age, equating to nearly 400,000 children born annually. Key factors influencing diagnostic yield include the sex of the affected individual, parental relatedness, and parental age. The study found that males are less likely to carry pathogenic DNMs, and individuals with affected family members are less likely to have pathogenic DNMs. Paternal age was weakly associated with pathogenic DNMs, but a strong paternal age effect was confirmed when analyzing all DNMs. The study identified 93 genes with genome-wide significance, including 80 with prior evidence of DD association. It also discovered 14 new genes with no prior evidence of DD causation. The study highlights the importance of considering de novo causation in all families. The prevalence of pathogenic missense and truncating DNMs was estimated at 41.8% of the cohort. The study also found that 59% of excess missense and truncating DNMs operate by loss-of-function mechanisms, while 41% by altered-function. The study estimated the birth prevalence of monoallelic developmental disorders at 1 in 295, highlighting the cumulative population morbidity and mortality of these disorders. The study emphasizes the need for larger studies and novel analytical strategies to discover remaining dominant developmental disorders. The integration of accurate phenotypic data improves the power to identify ultrarare DDs with distinctive clinical presentations. The study provides visual summaries of phenotypes associated with each gene and anonymized average face images for genome-wide significant genes. The study also highlights the importance of considering both loss-of-function and altered-function mechanisms in DDs. The findings underscore the role of de novo mutations in the genetic architecture of severe developmental disorders, with approximately half of these disorders attributed to loss-of-function and altered-function mechanisms. The study provides a comprehensive understanding of the prevalence, architecture, and mechanisms of de novo mutations in developmental disorders.