title: Target sequencing approach intended to discover new mutations in non-syndromic intellectual disability.
abstract: The technological improvements over the last years made considerable progresses in the knowledge of the etiology of intellectual Disability (ID). However, at present very little is known about the genetic heterogeneity underlying the non-syndromic form of ID (NS-ID). To investigate the genetic basis of NS-ID we analyzed 43 trios and 22 isolated NS-ID patients using a targeted sequencing (TS) approach. 71 NS-ID genes have been selected and sequenced in all subjects. We found putative pathogenic mutations in 7 out of 65 patients. The pathogenic role of mutations was evaluated through sequence comparison and structural analysis was performed to predict the effect of alterations in a 3D computational model through molecular dynamics simulations. Additionally, a deep patient clinical re-evaluation has been performed after the molecular results. This approach allowed us to find novel pathogenic mutations with a detection rate close to 11% in our cohort of patients. This result supports the hypothesis that many NS-ID related genes still remain to be discovered and that NS-ID is a more complex phenotype compared to syndromic form, likely caused by a complex and broad interaction between genes alterations and environment factors.
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Gandin
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Belcaro
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Palumbo
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Palumbo
authors.affiliation: Department of Pediatrics, University of Torino, Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Biamino
authors.affiliation: MOSE-DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Dal Col
authors.affiliation: MOSE-DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.affiliation: MOSE-DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: UOC Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, 94018 Troina, EN, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bosco
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: Department of Pediatrics, University of Torino, Torino, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
authors.affiliation: Unit of Pediatrics and Medical Genetics, IRCCS Associazione Oasi Maria Santissima, 94018 Troina, EN, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: Adamo Pio
authors.initials: AP
authors.lastname: d'Adamo
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Faletra
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy. Electronic address: diego.vozzi@burlo.trieste.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Vozzi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D000072260:RNA Splicing Factors; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000737:chemistry / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: C497837:ARID1B protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D017415:Ribonucleoprotein, U5 Small Nuclear; C506012:TXNL4A protein, human; D014157:Transcription Factors; C434066:WBP11 protein, human; D000255:Adenosine Triphosphate; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: Genetic diagnosis; Non-syndromic intellectual disability; Targeted sequencing