A large-scale study identified 12 novel genes associated with developmental disorders (DDs) in 1,133 children with undiagnosed severe DDs. Using exome sequencing and array-based chromosomal rearrangement detection, the researchers found that 12 new genes increased the diagnostic rate from 28% to 31%. These genes were linked to mutations that may disrupt normal development through activating or dominant-negative mechanisms. The study also revealed a significant burden of de novo copy number variants (CNVs) in DD children compared to controls, highlighting the importance of a genotype-driven approach in identifying rare genetic disorders. The study involved recruiting children from 24 regional genetics services in the UK and Ireland, with a majority of participants having Northwest European ancestry. The children exhibited a range of phenotypes, including intellectual disability, cranial MRI abnormalities, seizures, and congenital heart defects. The study combined exome sequencing, exome-aCGH, and genome-wide genotyping to detect mutations, identifying 1,618 de novo variants, of which 1,596 were validated. The study also identified 12 novel DD genes with strong evidence of pathogenicity, including PCGF2, DNM1, and TRIO, which were associated with distinct clinical phenotypes. The study found that females had a higher diagnostic yield of autosomal de novo mutations than males. The researchers also identified recurrent mutations in several genes, suggesting that these mutations may be involved in novel DDs. The study used a meta-analysis approach to combine data from multiple published studies, increasing the power to detect novel DD genes and highlighting shared genetic etiologies among neurodevelopmental disorders. The study also explored the functional roles of candidate genes using zebrafish models, revealing that many of these genes were involved in developmental processes. The study found that mutations in certain genes, such as COL4A3BP and PPP2R1A, may have a dominant-negative effect, disrupting normal development. The study concluded that a genotype-driven approach is particularly effective for identifying novel DDs with variable or indistinct clinical presentations. The findings underscore the importance of large-scale, comprehensive studies in uncovering the genetic causes of rare disorders.A large-scale study identified 12 novel genes associated with developmental disorders (DDs) in 1,133 children with undiagnosed severe DDs. Using exome sequencing and array-based chromosomal rearrangement detection, the researchers found that 12 new genes increased the diagnostic rate from 28% to 31%. These genes were linked to mutations that may disrupt normal development through activating or dominant-negative mechanisms. The study also revealed a significant burden of de novo copy number variants (CNVs) in DD children compared to controls, highlighting the importance of a genotype-driven approach in identifying rare genetic disorders. The study involved recruiting children from 24 regional genetics services in the UK and Ireland, with a majority of participants having Northwest European ancestry. The children exhibited a range of phenotypes, including intellectual disability, cranial MRI abnormalities, seizures, and congenital heart defects. The study combined exome sequencing, exome-aCGH, and genome-wide genotyping to detect mutations, identifying 1,618 de novo variants, of which 1,596 were validated. The study also identified 12 novel DD genes with strong evidence of pathogenicity, including PCGF2, DNM1, and TRIO, which were associated with distinct clinical phenotypes. The study found that females had a higher diagnostic yield of autosomal de novo mutations than males. The researchers also identified recurrent mutations in several genes, suggesting that these mutations may be involved in novel DDs. The study used a meta-analysis approach to combine data from multiple published studies, increasing the power to detect novel DD genes and highlighting shared genetic etiologies among neurodevelopmental disorders. The study also explored the functional roles of candidate genes using zebrafish models, revealing that many of these genes were involved in developmental processes. The study found that mutations in certain genes, such as COL4A3BP and PPP2R1A, may have a dominant-negative effect, disrupting normal development. The study concluded that a genotype-driven approach is particularly effective for identifying novel DDs with variable or indistinct clinical presentations. The findings underscore the importance of large-scale, comprehensive studies in uncovering the genetic causes of rare disorders.