FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.


Mitter D1, Pringsheim M2,3, Kaulisch M4, Plümacher KS5, Schröder S5, Warthemann R5, Abou Jamra R1, Baethmann M6, Bast T7, Büttel HM8, Cohen JS9, Conover E10, Courage C11, Eger A12, Fatemi A9, Grebe TA13, Hauser NS14, Heinritz W15, Helbig KL16, Heruth M17, Huhle D18, Höft K19, Karch S20, Kluger G2,3, Korenke GC21, Lemke JR1, Lutz RE10, Patzer S22, Prehl I23, Hoertnagel K23, Ramsey K24, Rating T25, Rieß A26, Rohena L27, Schimmel M28, Westman R29, Zech FM30, Zoll B31, Malzahn D32, Zirn B33, Brockmann K34.
  1. Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
  2. Klinik für Neuropädiatrie und Neurologische Rehabilitation, Epilepsiezentrum für Kinder und Jugendliche, Schön Klinik Voogtareuth, Vogtareuth, Germany.
  3. PMU Salzburg, Salzburg, Austria.
  4. Department für Forschungs- und Transferservice, Univeristät Leipzig, Leipzig, Germany.
  5. Klinik für Kinder- und Jugendmedizin, Universitätsmedizin Göttingen, Göttingen, Germany.
  6. Kinderklinik, Klinikum Dritter Orden, Munich, Germany.
  7. Epilepsiezentrum Kork, Kehl-Kork, Germany.
  8. Sozialpädiatrisches Zentrum, SLK-Kliniken Heilbronn, Heilbronn, Germany.
  9. Moser Center for Leukodystrophies and Neurogenetics Service, Kennedy Krieger Institute, Johns Hopkins Medical Institution, Baltimore, Maryland, USA.
  10. Department of Genetic Medicine, Munre Meyer Institute, University of nebraska medical Center Omaha, Omaha, Nebraska, US.
  11. Division of Human Genetics, Departmentof pediatrics, Inselspital, University of Bern, Bern, Switzerland.
  12. Sozialpädiatrisches Zentrum Leipzig (Frühere Hilfe Leipzig), Leipzig, Germany.
  13. Division of Genetics and Metabolism, Phoenix Children’s Hospital Phoenix, Arizona, USA.
  14. Department of Medical Genomics Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, Virginia, USA.
  15. Praxis für Humangenetik Cottbus, Cottbus, Germany.
  16. Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
  17. Klinik für Kinder- und Jugendmedizin, Sana Kliniken Leipziger Land, Borna, Germany.
  18. Praxis für Humangenetik Leipzig, Leipzig, Germany.
  19. Klinik für Kinder- und Jugendmedizin, Klinikum Magdeburg, Magdeburg, Germany.
  20. Sozialpädiatrisches Zentrum, Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Heidelberg, Heidelberg, Germany.
  21. Klinik für Neuropädiatrie und Angeborene Stoffwechselerkrankungen, Elisabeth Kinderkrankenhaus, klinikum Oldenburg, Oldenburg, Germany.
  22. Klinik für Kinder- und Jugendmedizin, Krankenhaus St. Elisabeth und St. Barbara, Halle/Saale, Germany.
  23. CeGaT, Tübingen, Germany.
  24. Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, USA.
  25. Sozialpädiatrisches Institut, Klinikum Bremen-Mitte, Bremen-Mitte, Germany.
  26. Institut für Medizinische Genetik und Angewandte Genomik, Universitätsklinikum Tübingen, Tübingen, Germany.
  27. Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.
  28. Klinik für Kinder und Jugendliche, Klinikum Augsburg, Augsburg, Germany.
  29. Children’s Specialty Center, St. Luke’s Children’s hospital, Boise, Idaho, USA.
  30. Klinik für Kinder- und Jugendmedizin, St. Vincenz-Krankenhaus Paderborn, Paderborn, Germany.
  31. Institut für Humangenetik, Universitätsmedizin Göttingen, Göttingen, Germany.
  32. Department of Genetic Epidemiology, Universtiy Medical Center, Georg-August University Göttingen, Göttingen, Germany.
  33. Genetic Counselling and Diagnostic, genetikum Stuttgart, Stuttgart, Stuttgart, Germany.
  34. SPZ, Klinik für Kinder- und Jugendmedizin Universitätsmedizin Göttingen, Göttingen, Germany.


PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher’s exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.