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

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.

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Acknowledgements

We sincerely thank the patient and family members for participation in this study, K. Hoffmann for technical assistance, S. Freier and H. Madle for help with cell culture, and RZPD for providing BAC clones and the FOXG1B cDNA clone. This work was supported by the German Human Genome Program (DHGP, grant number 01KW99087), by the National Genome Research Network (NGFN, project number 01GR0105), and in part by the Else Kroener-Fresenius-Stiftung (C.S-A.). The Wilhelm Johannsen Centre for Functional Genome Research was established by the Danish National Research Foundation.

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Correspondence to Vera M. Kalscheuer.

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Shoichet, S.A., Kunde, S., Viertel, P. et al. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly. Hum Genet 117, 536–544 (2005). https://doi.org/10.1007/s00439-005-1310-3

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Keywords

  • FOXG1
  • Agenesis of the corpus callosum
  • Microcephaly
  • Chromosome 14
  • Balanced translocation
  • Mental retardation
  • BF-1