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The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis
  1. Fanny Kortüm1,
  2. Soma Das2,
  3. Max Flindt1,
  4. Deborah J Morris-Rosendahl3,
  5. Irina Stefanova4,
  6. Amy Goldstein5,
  7. Denise Horn6,
  8. Eva Klopocki6,
  9. Gerhard Kluger7,
  10. Peter Martin8,
  11. Anita Rauch9,10,
  12. Agathe Roumer11,
  13. Sulagna Saitta12,
  14. Laurence E Walsh13,
  15. Dagmar Wieczorek14,
  16. Gökhan Uyanik1,15,
  17. Kerstin Kutsche1,
  18. William B Dobyns16
  1. 1Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  2. 2Department of Human Genetics, University of Chicago, Chicago, Illinois, USA
  3. 3Institute for Human Genetics, University Clinic Freiburg, Freiburg, Germany
  4. 4Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
  5. 5Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
  6. 6Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Berlin, Germany
  7. 7Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany
  8. 8Séguin Clinic, Epilepsy Center Kork, Kehl-Kork, Germany
  9. 9Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany
  10. 10Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  11. 11Sozialpädiatrisches Zentrum Frankfurt Mitte, Frankfurt, Germany
  12. 12Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  13. 13Department of Medical Genetics, Indiana University, Indianapolis, Indiana, USA
  14. 14Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
  15. 15Klinik und Poliklinik für Neurologie, Universität Regensburg, Regensburg, Germany
  16. 16Department of Pediatrics, University of Washington, and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA
  1. Correspondence to Kerstin Kutsche, Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Campus Forschung, Martinistraße 52, 20246 Hamburg, Germany; kkutsche{at} and William B Dobyns, Seattle Children's Research Institute Center for Integrative Brain Research, 1900 Ninth Avenue, M/S C9S-10, Seattle WA 98101, USA; wbd{at}


Background Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients.

Method The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals.

Results One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria.

Conclusions These findings have significantly expanded the number of FOXG1 mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.

  • Rett syndrome
  • FOXG1
  • mental retardation
  • microcephaly
  • clinical genetics

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  • Funding This work was supported by grants from the Werner Otto-Stiftung (WOS 3/76 to GU); the Deutsche Forschungsgemeinschaft (DFG) (GRK1459 to KK); and the National Institutes of Health (NIH) (1R01-NS058721 to WBD). This work was part of the German Mental Retardation Network (MRNET) funded through a grant from the German Ministry of Research and Education to A Rauch (01GS08160) and DW (01GS08164).

  • Competing interests None.

  • Patient consent Parental consents obtained.

  • Ethics approval This study was conducted with the approval of the University of Chicago, University of Lübeck, and University Hospital Center Hamburg-Eppendorf.

  • Provenance and peer review Not commissioned; externally peer reviewed.