The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

Fanny Kortüm (1) , Soma Das (2) , Max Flindt (1) , Deborah J. Morris-Rosendahl (3) , Irina Stefanova (4) , Amy Goldstein (5) , Denise Horn (6) , Eva Klopocki (6) , Gerhard Kluger (7) , Peter Martin (8) , Anita Rauch (9) , Agathe Roumer (10) , Sulagna Saitta (11) , Laurence Walsh (12) , Dagmar Wieczorek (13) , Gökhan Uyanik (1) , Kerstin Kutsche (1) , William Dobyns (14)

1 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
2 University of Chicago
3 University Clinic Freiburg
4 Universität zu Lübeck = University of Lübeck [Lübeck]
5 Children's Hospital of Pittsburgh
6 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
7 Epilepsy Center for Children and Adolescents
8 Epilepsy Center Kork
9 Allergy Unit - Department of Dermatology
10 Sozialpädiatrisches Zentrum Frankfurt Mitte
11 CHOP - Children’s Hospital of Philadelphia
12 Indiana University
13 Universitätsklinikum Essen
14 Seattle Children's Research Institute

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. We aimed to further characterize and delineate the phenotype of FOXG1-mutation positive patients. Method: We mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridization and analyzed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array CGH. We sequenced the FOXG1 gene in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2-mutation negative individuals. Results: We report one known mutation, seen in 2 patients, and 9 novel mutations of FOXG1 including 2 deletions, 2 chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and 7 sequence changes. Analysis of our 11 patients, and 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 gastroesophageal 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: We 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 recognizable phenotype which we suggest to designate as the FOXG1 syndrome.

Mots clés: Clinical genetics

Fanny Kortüm, Soma Das, Max Flindt, Deborah J. Morris-Rosendahl, Irina Stefanova, et al.. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. Journal of Medical Genetics, 2011, 48 (6), pp.396. ⟨10.1136/jmg.2010.087528⟩. ⟨hal-00616882⟩