Human Genetics

, Volume 117, Issue 6, pp 536–544

Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly

  • Sarah A. Shoichet
  • Stella-Amrei Kunde
  • Petra Viertel
  • Can Schell-Apacik
  • Hubertus von Voss
  • Niels Tommerup
  • Hans-Hilger Ropers
  • Vera M. Kalscheuer
Original Investigation

DOI: 10.1007/s00439-005-1310-3

Cite this article as:
Shoichet, S.A., Kunde, SA., Viertel, P. et al. Hum Genet (2005) 117: 536. doi:10.1007/s00439-005-1310-3

Abstract

We have investigated the chromosome abnormalities in a female patient exhibiting a severe cognitive disability associated with complete agenesis of the corpus callosum and microcephaly. The patient carries a balanced de novo translocation t(2;14)(p22;q12), together with a neighbouring 720 kb inversion in chromosome 14q12. By combined fluorescence in situ hybridisation and Southern hybridisation, the distal inversion breakpoint on chromosome 14 was mapped to a region harbouring genes and ESTs derived predominantly from brain tissue. RT-PCR studies indicated that these transcripts comprise the 3′ ends of novel splice variants of the winged helix transcription factor FOXG1B (also referred to in previous studies as FOXG1A and FOXG1C, as well as Brain Factor 1), the mouse orthologue of which is essential for normal development of the telencephalon. Analysis of these novel FOXG1B transcripts indicated that they are all disrupted by the breakpoint in the patient. Moreover, we have identified novel orthologous Foxg1 transcripts in the mouse and other vertebrates, which validates the functional importance of these variants and provides a direct genetic link between the patient phenotype and that of the heterozygous Foxg1 knockout mice. These results, together with previously published studies on patients with similar disorders and proximal 14q deletions, strongly suggest that several disorders associated with malformations of the human brain may be directly caused by mutations or alterations in the FOXG1B gene.

Keywords

FOXG1Agenesis of the corpus callosumMicrocephalyChromosome 14Balanced translocationMental retardationBF-1

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Sarah A. Shoichet
    • 1
  • Stella-Amrei Kunde
    • 1
  • Petra Viertel
    • 1
  • Can Schell-Apacik
    • 2
  • Hubertus von Voss
    • 2
  • Niels Tommerup
    • 3
  • Hans-Hilger Ropers
    • 1
  • Vera M. Kalscheuer
    • 1
  1. 1.Max-Planck-Institute for Molecular GeneticsBerlinGermany
  2. 2.Medizinische GenetikKinderzentrum MünchenMunichGermany
  3. 3.Department of Medical Biochemistry and Genetics, Wilhelm Johannsen Centre for Functional Genome ResearchThe Panum InstituteCopenhagenDenmark