Neurodevelopmental disorders (NDD) refer to a group of conditions resulting from disturbances of the developing brain with a typical onset in childhood before puberty. Genetic causes make up a large part of developmental delays, which is why genetic examinations play a decisive role in the clarification of the causes of NDD. Due to the development of Next Generation Sequencing (NGS) and the increased use of genome-wide analyses in recent years, it has become clear that a large proportion of cases are due to rare, monogenic alterations in each case. Meanwhile, 1534 genes have been currently associated with NDD. Nevertheless, half of the evaluated cases remain without a valid diagnosis. However, this is a prerequisite for personalized support and the estimation of the development prognosis, as well as the differentiated assessment of the risk of recurrence for family members. To decipher the genetics of NDD, I systematically analyzed the exome sequences of 104 individuals with NDD and their relatives (see Figure 2). In 10 of the 104 cases, I was able to find variants in already known genes that partially explain the phenotype. I intensively evaluated all the cases for new candidate genes and identified 89 candidate genes in 58 individuals (see Supplementary, Table S1). In the remaining 46 individuals, no candidate gene could be identified. I then scored the candidate genes to prioritize them regarding the probability of being true NDD genes. From the detailed analysis of a relatively small cohort of NDD individuals (n=104) and the resulting 89 candidate genes, a total of 9 research collaborations have emerged (see Table 1). Of the candidate genes with further research in AutoCasC, six are in my top 20 candidate genes, which is a good indication of the efficiency of this systematic approach on deciphering the genetics of NDD. Studies on the candidate genes SKOR2, HCN2, SP9, CCDC66, and TANC1 are currently being worked on by collaborators worldwide and we could add our clinical and genetic data (see Table 1). Further, I was more substantially involved in the identification of the candidate gene ATP2B1, subsequently studied functionally, and published in the American Journal of Human Genetics (IF 11,0) with me as coauthor as a novel NDD gene, and the ongoing research on a genotype-phenotype correlation with functional lines of evidence of NDD-individuals with variants in DOCK4. Furthermore, I have led the efforts for the genes RIPPLY2 and PABPC1. I was able to describe three individuals from two families with compound-heterozygous variants in RIPPLY2 in two sisters and a homozygous nonsense variant in an 8-year-old boy. All individuals had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of spondylocostal dysostosis 6 (SCDO6) including scoliosis, mild facial asymmetry, spinal spasticity, and hemivertebrae. At this time, RIPPLY2 was only associated as a candidate gene with SCDO6 and had only been described in a small cohort of seven individuals from five families in two publications. I could confirm that bi-allelic variants in RIPPLY2 cause congenital cervical spine malformation in spondylocostal dysostosis type 6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum as a first author in a publication published in Clinical Genetics (IF 4,4). In the study on PABPC1, I describe four individuals with an overlapping phenotype of developmental delay, expressive speech delay, autistic features, and heterozygous de novo variants that cluster in the PABP domain of PABPC1. Further symptoms are seizures and behavioral disorders. Molecular modeling predicted that the variants are pathogenic and would lead to decreased binding affinity to mRNA metabolism-related proteins such as PAIP2. Co-immunoprecipitation confirmed this as it demonstrated a significant weakening of the interaction between mutant PABPC1 and PAIP2. Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. The wild type Pabpc1 could rescue this disturbance, while three of the four variants did not. Together with partners from the Central South University in Changsha, China, I was able to propose that pathogenic missense variants in the PABP-domain of PABPC1 lead to a novel form of developmental disorder and published my work in Genetics in Medicine (IF 8,9). Through this, I demonstrated that systematic trio exome analysis and identification and characterization of candidate genes followed by prioritizing the genes based on systematic scoring and by building international cooperation to gather further individuals, describe the phenotypes, and prove that the pathogenicity of the variants is an excellent way to decipher the genetics of NDD. With this approach, I was able to describe PABPC1 as a novel NDD-gene and confirm the association between RIPPLY2 and SCDO6. Moreover, I contributed as a co-author to the publication of ATP2B1 as a novel NDD-gene and to the ongoing research on SKOR2, SP9, HCN2, CCDC66, TANC1, and DOCK4. More might follow in the future. The continuation of this research in genetic diagnostics is important for creating personalized support and prevention programs for individuals with neurodevelopmental delays, to be able to estimate the developmental prognosis, and to be able to assess the recurrence risk of other family members in a more differentiated way.:1 Introduction 1.1 Genetics of neurodevelopmental disorders 1.2 Identification of neurodevelopmental delay genes 1.3 Assessment of candidate genes 1.4 Rationale 1.5 Results 1.5.1 Identification of neurodevelopmental delay genes 1.5.2 Scoring of the identified candidate genes 1.5.3 Candidate genes under further research 2 Publications 2.1 Congenital cervical spine malformation due to bi-allelic RIPPLY2 variants in spondylocostal dysostosis type 6 2.2 De novo variants in the PABP-domain of PABPC1 lead to developmental delay 3 Summary 4 References 5 Internet resources 6 Supplementary 7 Presentation of personal scientific contribution 8 Declaration of Authorship