title: Identification of novel genetic causes of Rett syndrome-like phenotypes.
abstract: 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.
  
  
  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.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Lopes
authors.affiliation: Department of Genetics and Genomic Sciences, The Mindich Child Health & Development Institute, The Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Barbosa
authors.affiliation: Science for Life Laboratory Uppsala, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Ameur
authors.affiliation: Center for Medical Genetics Dr. Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Soares
authors.affiliation: Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Joaquim
authors.initials: J
authors.lastname: de Sá
authors.affiliation: Serviço de Neurologia Pediátrica, Hospital D. Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Dias
authors.affiliation: Unidade de Neurodesenvolvimento e Autismo, Centro de Desenvolvimento da Criança e Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal Faculty of Medicine, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, University of Coimbra, Coimbra, Portugal.
authors.forename: Guiomar
authors.initials: G
authors.lastname: Oliveira
authors.affiliation: Department of Neurology, Egas Moniz Hospital, Lisbon, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabral
authors.affiliation: Department of Neuropediatrics, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Temudo
authors.affiliation: Serviço de Neurologia Pediátrica, Hospital D. Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal.
authors.forename: Eulália
authors.initials: E
authors.lastname: Calado
authors.affiliation: Centro de Desenvolvimento Luís Borges, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Isabel Fineza
authors.initials: IF
authors.lastname: Cruz
authors.affiliation: Serviço de Neurologia Pediátrica, Hospital D. Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal.
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Vieira
authors.affiliation: Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Renata
authors.initials: R
authors.lastname: Oliveira
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Esteves
authors.affiliation: Otto-Warburg-Laboratory, Max-Planck-Institute for Molecular Genetics, Berlin, Germany CU Systems Medicine, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Science for Life Laboratory Uppsala, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Jonasson
authors.affiliation: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Science for Life Laboratory Uppsala, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.affiliation: Department of Genetics and Genomic Sciences, The Mindich Child Health & Development Institute, The Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Maciel
mesh_terms: D055028:Comparative Genomic Hybridization; D059472:Exome; D005260:Female; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics*
keywords: Epilepsy; Intellectual disability; Rett syndrome; Whole exome sequencing