IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?
IQSEC2
Rett syndrome
intellectual disability
phenotype-genotype
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
03
10
2020
revised:
12
12
2020
accepted:
22
12
2020
pubmed:
29
12
2020
medline:
1
1
2022
entrez:
28
12
2020
Statut:
ppublish
Résumé
IQSEC2 mutations are associated with IQSEC2-related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype-phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2-related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype-phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate-to-mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2-associated phenotype delineation.
Substances chimiques
Guanine Nucleotide Exchange Factors
0
IQSEC2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
462-474Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Hinze SJ, Jackson MR, Lie S, et al. Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis. Transl Psychiatry. 2017;7:e1110. https://doi.org/10.1038/tp.2017.81.
Morleo M, Franco B. Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders. J Med Genet. 2008;45:401-408. https://doi.org/10.1136/jmg.2008.058305.
Tarpey PS, Smith R, Pleasance E, et al. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet. 2009;41:535-543. https://doi.org/10.1038/ng.367.
Shoubridge C, Tarpey PS, Abidi F, et al. Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat Genet. 2010;42:486-488. https://doi.org/10.1038/ng.588.
Gandomi SK, Farwell Gonzalez KD, Parra M, et al. Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for genetic counseling and clinical diagnosis. J Genet Couns. 2014;23:289-298. https://doi.org/10.1007/s10897-013-9671-6.
Zerem A, Haginoya K, Lev D, et al. The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia. 2016;57:1858-1869. https://doi.org/10.1111/epi.13560.
Allou L, Julia S, Amsallem D, et al. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease. Clin Genet. 2017;91:431-440. https://doi.org/10.1111/cge.12784.
Olson HE, Tambunan D, Lacoursiere C, et al. Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome. Am J Med Genet Part A. 2015;167:2017-2025. https://doi.org/10.1002/ajmg.a.37132.
Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68:944-950. https://doi.org/10.1002/ana.22124.
Renieri A, Mari F, Mencarelli MA, et al. Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant). Brain Dev. 2009;31:208-216. https://doi.org/10.1016/j.braindev.2008.04.007.
Neul JL, Lane JB, Lee HS, et al. Developmental delay in Rett syndrome: data from the natural history study. J Neurodev Disord. 2014;6:20. https://doi.org/10.1186/1866-1955-6-20.
Philippe C, Amsallem D, Francannet C, et al. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J Med Genet. 2010;47:59-65. https://doi.org/10.1136/jmg.2009.067355.
Mitter D, Pringsheim M, Kaulisch M, et al. FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants. Genet Med. 2018;20:98-108. https://doi.org/10.1038/gim.2017.75.
Parrini E, Marini C, Mei D, et al. Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Hum Mutat. 2017;38(2):216-225. https://doi.org/10.1002/humu.23149.
Shoubridge C, Harvey RJ, Dudding-Byth T. IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy. Hum Mutat. 2019;40:5-24. https://doi.org/10.1002/humu.23670.
Mignot C, McMahon AC, Bar C, et al. IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients. Genet Med. 2019;21:837-849. https://doi.org/10.1038/s41436-018-0268-1.
Radley JA, O'Sullivan RBG, Turton SE, et al. Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype. Clin Genet. 2019;95:496-506. https://doi.org/10.1111/cge.13507.
Barrie ES, Cottrell CE, Gastier-Foster J, et al. Genotype-phenotype correlation: inheritance and variant-type infer pathogenicity in IQSEC2 gene. Eur J Med Genet. 2020;63:103735. https://doi.org/10.1016/j.ejmg.2019.103735.
Zou Q, Zheng J, Zhang R, Fang Y, Cai C. A case of intellectual disability reveals a novel mutation in IQSEC2 gene by whole exome sequencing. Psychiatr Genet. 2019;29:243-247.
Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434:400-404. https://doi.org/10.1038/nature03479.
Cotton AM, Price EM, Jones MJ, Balaton BP, Kobor MS, Brown CJ. Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation. Hum Mol Genet. 2015;24:1528-1539. https://doi.org/10.1093/hmg/ddu564.
Moey C, Hinze SJ, Brueton L, et al. Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders. Eur J Hum Genet. 2016;24:373-380. https://doi.org/10.1038/ejhg.2015.123.
Tukiainen T, Villani AC, Yen A, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550:244-248. https://doi.org/10.1038/nature24265.
Landucci E, Brindisi M, Bianciardi L, et al. iPSC-derived neurons profiling reveals GABAergic circuit disruption and acetylated α-tubulin defect which improves after iHDAC6 treatment in Rett syndrome. Exp Cell Res. 2018;368:225-235. https://doi.org/10.1016/j.yexcr.2018.05.001.
Sah M, Shore AN, Petri S, et al. Altered excitatory transmission onto hippocampal interneurons in the IQSEC2 mouse model of X-linked neurodevelopmental disease. Neurobiol Dis. 2020;137:104758. https://doi.org/10.1016/j.nbd.2020.104758.
Patrizi A, Awad PN, Chattopadhyaya B, Li C, Di Cristo G, Fagiolini M. Accelerated hyper-maturation of Parvalbumin circuits in the absence of MeCP2. Cereb Cortex. 2020;30:256-268. https://doi.org/10.1093/cercor/bhz085.
Mari F, Azimonti S, Bertani I, et al. CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum Mol Genet. 2005;14:1935-1946. https://doi.org/10.1093/hmg/ddi198.