a272fa9df1141827201fcdb6962ddd0a pmc_10048137.pdf 97af1e91f26d49d6c45291188cf86e81f5299d8c pmc_10048137.pdf 42161d77a97258b9438a54007e074436f5c1c291f79ed8ef7184c1d7efedf351 pmc_10048137.pdf Title: High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders Subject: Neurodevelopmental disorders (NDDs) affect 2–5% of the population and approximately 50% of cases are due to genetic factors. 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). Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering. Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. 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. No differences in diagnostic rates were found between patients affected by different levels of ID severity. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant. Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. 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. Keywords: neurodevelopmental disorders; intellectual disability; autism; gene panel; next generation sequencing; re-analysis Author: Nino Spataro, Juan Pablo Trujillo-Quintero, Carmen Manso, Elisabeth Gabau, Nuria Capdevila, Victor Martinez-Glez, Antoni Berenguer-Llergo, Sara Reyes, Anna Brunet, Neus Baena, Miriam Guitart and Anna Ruiz Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Mar 22 03:16:21 2023 CET ModDate: Wed Mar 22 03:18:11 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 896990 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CIQLLF+VnURWPalladioL Type 1 Custom yes yes no 10 0 FAGAQF+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 QGVPIA+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 RHBPET+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 KONDUX+EuphemiaUCAS-Bold Type 1C WinAnsi yes yes no 42 0 HIZBRM+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 45 0 IKAMBL+CMSY10 Type 1 Builtin yes yes no 70 0 EUAQDG+EURM10 Type 1 Builtin yes yes no 74 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-07-29 02:32:27 CEST RepresentationInformation: pmc_10048137.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-07-28 02:24:06 CEST Size: 896990 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 297 FreeObjects: 3 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Patients Description and Classification Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Gene Panel Content Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Sequencing and Data Processing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Variant Filtering Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Re-Analysis Variant Filtering Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Copy Number Variants Detection and Filtering Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Exome Sequencing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Variant Validation and Classification Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: Diagnostic Yield, Variant Types, and Genes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Data Re-Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Sex and Patient Subset Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Clinical Profiling Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: WES Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Info: Title: High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders Author: Nino Spataro, Juan Pablo Trujillo-Quintero, Carmen Manso, Elisabeth Gabau, Nuria Capdevila, Victor Martinez-Glez, Antoni Berenguer-Llergo, Sara Reyes, Anna Brunet, Neus Baena, Miriam Guitart and Anna Ruiz Subject: Neurodevelopmental disorders (NDDs) affect 2 5% of the population and approximately 50% of cases are due to genetic factors. 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). Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering. Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. 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. No differences in diagnostic rates were found between patients affected by different levels of ID severity. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant. Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. 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. 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