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Identification of novel genetic causes of Rett syndrome-like phenotypes
Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA.;Inst Gulbenkian Ciencias, Oeiras, Portugal..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Ctr Hosp Porto, Ctr Med Genet Dr Jacinto Magalhaes, Oporto, Portugal..
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2016 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 53, no 3, 190-199 p.Article in journal (Refereed) PublishedText
Abstract [en]

Background The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. Methods and results We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Conclusions Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

Place, publisher, year, edition, pages
2016. Vol. 53, no 3, 190-199 p.
Keyword [en]
Rett syndrome, Epilepsy, Whole exome sequencing, Intellectual disability
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-282471DOI: 10.1136/jmedgenet-2015-103568ISI: 000371329600006PubMedID: 26740508OAI: oai:DiVA.org:uu-282471DiVA: diva2:917166
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2016-04-05Bibliographically approved

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Ameur, AdamJonasson, IngerSyvänen, Ann-ChristineGyllensten, Ulf
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Department of Immunology, Genetics and PathologyMolecular MedicineMedicinsk genetik och genomik
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