J Med Genet 47:59-65 doi:10.1136/jmg.2009.067355
  • Short report

Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females

  1. C Philippe1,
  2. D Amsallem2,
  3. C Francannet3,
  4. L Lambert4,
  5. A Saunier1,
  6. F Verneau1,
  7. P Jonveaux1
  1. 1Laboratoire de Génétique Médicale, Nancy Université, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France
  2. 2Service de Neuropédiatrie, Hôpital St Jacques, Besançon, France
  3. 3Service de Génétique Médicale, CHU Hôtel-Dieu, Clermont-Ferrand I, France
  4. 4Service de Médecine Infantile 1, Hôpital d'Enfants, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France
  1. Correspondence to Dr C Philippe, Laboratoire de Génétique Médicale, Nancy Université, EA 4002, Centre Hospitalier Régional et Universitaire, Rue du Morvan, 54511 cedex 1, Vandoeuvre-les-Nancy, France; c.philippe{at}
  • Received 24 February 2009
  • Revised 20 April 2009
  • Accepted 29 April 2009
  • Published Online First 29 June 2009


Background The FOXG1 gene has been recently implicated in the congenital form of Rett syndrome (RTT). It encodes the fork-head box protein G1, a winged-helix transcriptional repressor with expression restricted to testis and brain, where it is critical for forebrain development. So far, only two point mutations in FOXG1 have been reported in females affected by the congenital form of RTT.

Aim To assess the involvement of FOXG1 in the molecular aetiology of classical RTT and related disorders.

Methods The entire multi-exon coding sequence of FOXG1 was screened for point mutations and large rearrangements in a cohort of 35 MECP2/CDKL5 mutation-negative female patients including 31 classical and four congenital forms of RTT.

Results Two different de novo heterozygous FOXG1-truncating mutations were identified. The subject with the p.Trp308X mutation presented with a severe RTT-like neurodevelopmental disorder, whereas the p.Tyr400X allele was associated with a classical clinical RTT presentation.

Conclusions These new cases give additional support to the genetic heterogeneity in RTT and help to delineate the clinical spectrum of the FOXG1-related phenotypes. FOXG1 screening should be considered in the molecular diagnosis of RTT.


  • Funding This study was supported by a grant from GIS-Institut des Maladies Rares.

  • Competing interests None.

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