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Original article
Identification of novel genetic causes of Rett syndrome-like phenotypes
  1. Fátima Lopes1,2,
  2. Mafalda Barbosa3,4,
  3. Adam Ameur5,
  4. Gabriela Soares6,
  5. Joaquim de Sá7,
  6. Ana Isabel Dias8,
  7. Guiomar Oliveira9,10,
  8. Pedro Cabral11,
  9. Teresa Temudo12,
  10. Eulália Calado8,
  11. Isabel Fineza Cruz13,
  12. José Pedro Vieira8,
  13. Renata Oliveira7,
  14. Sofia Esteves1,2,
  15. Sascha Sauer14,15,
  16. Inger Jonasson5,
  17. Ann-Christine Syvänen16,
  18. Ulf Gyllensten5,
  19. Dalila Pinto3,
  20. Patrícia Maciel1,2
  1. 1Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
  2. 2ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
  3. 3Department 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
  4. 4Instituto Gulbenkian de Ciência, Oeiras, Portugal
  5. 5Science for Life Laboratory Uppsala, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  6. 6Center for Medical Genetics Dr. Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal
  7. 7Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
  8. 8Serviço de Neurologia Pediátrica, Hospital D. Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal
  9. 9Unidade 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
  10. 10Faculty of Medicine, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, University of Coimbra, Coimbra, Portugal
  11. 11Department of Neurology, Egas Moniz Hospital, Lisbon, Portugal
  12. 12Department of Neuropediatrics, Centro Hospitalar do Porto, Porto, Portugal
  13. 13Centro de Desenvolvimento Luís Borges, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
  14. 14Otto-Warburg-Laboratory, Max-Planck-Institute for Molecular Genetics, Berlin, Germany
  15. 15CU Systems Medicine, University of Wuerzburg, Wuerzburg, Germany
  16. 16Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  1. Correspondence to Professor Patricia Maciel, Life and Health Sciences Research Institute—School of Health Sciences, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal; pmaciel{at}


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.

  • Rett syndrome
  • Epilepsy
  • Whole exome sequencing
  • Intellectual disability

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