FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants

Diana Mitter, Milka Pringsheim, Marc Kaulisch, Kim Sarah Plümacher, Simone Schröder, Rita Warthemann, Rami Abou Jamra, Martina Baethmann, Thomas Bast, Hans Martin Büttel, Julie S. Cohen, Elizabeth Conover, Carolina Courage, Angelika Eger, Ali Fatemi, Theresa A. Grebe, Natalie S. Hauser, Wolfram Heinritz, Katherine L. Helbig, Marion HeruthDagmar Huhle, Karen Höft, Stephanie Karch, Gerhard Kluger, G. Christoph Korenke, Johannes R. Lemke, Richard E. Lutz, Steffi Patzer, Isabelle Prehl, Konstanze Hoertnagel, Keri Ramsey, Tina Rating, Angelika Rieß, Luis Rohena, Mareike Schimmel, Rachel Westman, Frank Martin Zech, Barbara Zoll, Dörthe Malzahn, Birgit Zirn, Knut Brockmann

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)98-108
Number of pages11
JournalGenetics in Medicine
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2018

Keywords

  • FOXG1 phenotypic spectrum
  • FOXG1 variants
  • congenital variant of Rett syndrome
  • genotype-phenotype association

ASJC Scopus subject areas

  • Genetics(clinical)

Fingerprint Dive into the research topics of 'FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants'. Together they form a unique fingerprint.

  • Cite this

    Mitter, D., Pringsheim, M., Kaulisch, M., Plümacher, K. S., Schröder, S., Warthemann, R., Abou Jamra, R., Baethmann, M., Bast, T., Büttel, H. M., Cohen, J. S., Conover, E., Courage, C., Eger, A., Fatemi, A., Grebe, T. A., Hauser, N. S., Heinritz, W., Helbig, K. L., ... Brockmann, K. (2018). FOXG1 syndrome: Genotype-phenotype association in 83 patients with FOXG1 variants. Genetics in Medicine, 20(1), 98-108. https://doi.org/10.1038/gim.2017.75