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      Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With “Developmental and Epileptic Encephalopathy”

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          Abstract

          SETBP1 mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of SETBP1, two novel de novo truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified SETBP1 variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C>T (p.Arg589 *) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19 *) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G>A (p.Glu858Lys) variant, which is absent from the control population, reported as de novo in a subject with ASD, and located close to the SETBP1 hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of SETBP1 in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to “developmental and epileptic encephalopathy” (DEE).

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          Most cited references26

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          ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

          High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .
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            CADD: predicting the deleteriousness of variants throughout the human genome

            Abstract Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. CADD uses a machine learning model trained on a binary distinction between simulated de novo variants and variants that have arisen and become fixed in human populations since the split between humans and chimpanzees; the former are free of selective pressure and may thus include both neutral and deleterious alleles, while the latter are overwhelmingly neutral (or, at most, weakly deleterious) by virtue of having survived millions of years of purifying selection. Here we review the latest updates to CADD, including the most recent version, 1.4, which supports the human genome build GRCh38. We also present updates to our website that include simplified variant lookup, extended documentation, an Application Program Interface and improved mechanisms for integrating CADD scores into other tools or applications. CADD scores, software and documentation are available at https://cadd.gs.washington.edu.
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              Synaptic, transcriptional, and chromatin genes disrupted in autism

              Summary The genetic architecture of autism spectrum disorder involves the interplay of common and rare variation and their impact on hundreds of genes. Using exome sequencing, analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, and a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic, transcriptional, and chromatin remodeling pathways. These include voltage-gated ion channels regulating propagation of action potentials, pacemaking, and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodelers, prominently histone post-translational modifications involving lysine methylation/demethylation.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                16 December 2020
                2020
                : 11
                : 593446
                Affiliations
                [1] 1Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova , Padua, Italy
                [2] 2Fondazione Istituto di Ricerca Pediatrica (IRP), Città Della Speranza , Padua, Italy
                [3] 3Paediatric Neurology and Neurophysiology Unit, Department of Woman and Child Health, University Hospital of Padova , Padua, Italy
                [4] 4Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ca' Granda Ospedale Maggiore Policlinico , Milan, Italy
                Author notes

                Edited by: Francesca Forzano, Guy's Hospital, United Kingdom

                Reviewed by: Miguel A. Barboza, University of Costa Rica, Costa Rica; Arianna Tucci, Genomics England, United Kingdom

                *Correspondence: Emanuela Leonardi emanuela.leonardi@ 123456unipd.it

                This article was submitted to Neurogenetics, a section of the journal Frontiers in Neurology

                †These authors have contributed equally to this work

                Article
                10.3389/fneur.2020.593446
                7772201
                33391157
                db9de6ac-73e5-4cbd-8c46-c6f3ce946c69
                Copyright © 2020 Leonardi, Bettella, Pelizza, Aspromonte, Polli, Boniver, Sartori, Milani and Murgia.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 August 2020
                : 16 November 2020
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 26, Pages: 9, Words: 6716
                Funding
                Funded by: Ministry of Public Health 10.13039/501100004397
                Funded by: Fondazione Città della Speranza 10.13039/100007363
                Award ID: 18-04
                Award ID: 19-12
                Categories
                Neurology
                Original Research

                Neurology
                setbp1,id,epilepsy,epileptic encephalopathy,ngs,gene panel,mrd29
                Neurology
                setbp1, id, epilepsy, epileptic encephalopathy, ngs, gene panel, mrd29

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