title: 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements.
abstract: The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (-4 to-6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.
authors: EA 4368, Déficiences mentales et anomalies de structure du génome, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France.
authors: Lila
authors: L
authors: Allou
authors: Laetitia
authors: L
authors: Lambert
authors: Daniel
authors: D
authors: Amsallem
authors: Eric
authors: E
authors: Bieth
authors: Patrick
authors: P
authors: Edery
authors: Anne
authors: A
authors: Destrée
authors: François
authors: F
authors: Rivier
authors: David
authors: D
authors: Amor
authors: Elizabeth
authors: E
authors: Thompson
authors: Julian
authors: J
authors: Nicholl
authors: Michael
authors: M
authors: Harbord
authors: Christophe
authors: C
authors: Nemos
authors: Aline
authors: A
authors: Saunier
authors: Aissa
authors: A
authors: Moustaïne
authors: Adeline
authors: A
authors: Vigouroux
authors: Philippe
authors: P
authors: Jonveaux
authors: Christophe
authors: C
authors: Philippe
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000175:diagnosis / Q000235:genetics; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D056915:DNA Copy Number Variations; D020820:Dyskinesias / Q000175:diagnosis / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020161:Physical Chromosome Mapping; D017354:Point Mutation; D011493:Protein Kinase C / Q000235:genetics; D015518:Rett Syndrome / Q000175:diagnosis / Q000235:genetics; D037941:Silencer Elements, Transcriptional / Q000235:genetics*; D013577:Syndrome; D014158:Transcription, Genetic
chemical_list: C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; C089212:protein kinase D; D011493:Protein Kinase C