TY - JOUR
T1 - Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With “Developmental and Epileptic Encephalopathy”
AU - Leonardi, Emanuela
AU - Bettella, Elisa
AU - Pelizza, Maria Federica
AU - Aspromonte, Maria Cristina
AU - Polli, Roberta
AU - Boniver, Clementina
AU - Sartori, Stefano
AU - Milani, Donatella
AU - Murgia, Alessandra
N1 - Funding Information:
This work was supported by Italian Ministry of Health Young Investigator (Grant GR-2011-02347754) and Fondazione Istituto di Ricerca Pediatrica—Città della Speranza (Grant 18-04 to EL and 19/12 to AM).
Publisher Copyright:
© Copyright © 2020 Leonardi, Bettella, Pelizza, Aspromonte, Polli, Boniver, Sartori, Milani and Murgia.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/16
Y1 - 2020/12/16
N2 - 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).
AB - 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).
KW - epilepsy
KW - epileptic encephalopathy
KW - gene panel
KW - ID
KW - MRD29
KW - NGS
KW - SETBP1
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U2 - 10.3389/fneur.2020.593446
DO - 10.3389/fneur.2020.593446
M3 - Article
AN - SCOPUS:85098481915
VL - 11
JO - Frontiers in Neurology
JF - Frontiers in Neurology
SN - 1664-2295
M1 - 593446
ER -