![]() To test whether clinical and demographic features could predict the absence/presence of a pathogenic variant, each single HPO term used was classified into 16 possible categories representing different affected systems or clinical entities. Consequently, the analysis of the genes related to these relevant molecular pathways may allow the identification of the pathogenic genetic factors in a significant proportion of NDDs cases. Several causal genes are shared among various NDDs and converge to a limited set of biological processes, such as those regulating synaptic plasticity, chromatin remodeling, gene transcription, and protein degradation. For instance, 70% of patients affected by autistic spectrum disorder (ASD) also show ID conversely, 40% of ID patients display ASD. ID is genetically highly heterogeneous and its genetic basis is shared with other NDDs, explaining in part their observed comorbidity. This fast-growing amount of information is stored in publicly accessible databases, such as SysNDD and SFARI, among others. Overall, sequencing-based approaches allow the identification of the causal genetic factor in ~30% of ID cases and facilitate the discovery of new causal genes. In the last decade, next-generation sequencing (NGS) technologies have been integrated into clinical practice and are being proposed as a first-tier approach for ID molecular diagnosis. For this reason, we propose the list of genes included in our customized gene panel and the variant filtering procedure presented here as a first-tier approach for the molecular diagnosis of NDDs in WES studies. Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant. ![]() No differences in diagnostic rates were found between patients affected by different levels of ID severity. As reported previously, a significantly higher diagnostic yield was observed: ( i) in patients affected by ID/GDD compared to those affected only by ASD, and ( ii) in females despite the higher proportion of males among our patients. Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering. Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. Since de novo pathogenic variants account for the majority of cases, a gene panel including 460 dominant and X-linked genes was designed and applied to 398 patients affected by intellectual disability (ID)/global developmental delay (GDD) and/or autism (ASD). Neurodevelopmental disorders (NDDs) affect 2–5% of the population and approximately 50% of cases are due to genetic factors.
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