Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy

Nancy Vegas, Mara Cavallin, Camille Maillard, Nathalie Boddaert, Joseph Toulouse, Elise Schaefer, Tally Lerman-Sagie, Dorit Lev, Barth Magalie, Sébastien Moutton, Eric Haan, Bertrand Isidor, Delphine Heron, Mathieu Milh, Stéphane Rondeau, Caroline Michot, Stephanie Valence, Sabrina Wagner, Marie Hully, Cyril MignotAlice Masurel, Alexandre Datta, Sylvie Odent, Mathilde Nizon, Leila Lazaro, Marie Vincent, Benjamin Cogné, Anne Marie Guerrot, Stéphanie Arpin, Jean Michel Pedespan, Isabelle Caubel, Benedicte Pontier, Baptiste Troude, Francois Rivier, Christophe Philippe, Thierry Bienvenu, Marie Aude Spitz, Amandine Bery, Nadia Bahi-Buisson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective To provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome. Methods We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations. Results A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations. Conclusions These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

Original languageEnglish
Article numbere281
JournalNeurology: Genetics
Issue number6
StatePublished - 1 Dec 2018
Externally publishedYes


FundersFunder number
Seventh Framework Programme602531
Agence Nationale de la RechercheANR-16-CE16-0011


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