Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

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


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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. Chong SS, Pack SD, Roschke AV, Tanigami A, Carrozzo R, Smith AC, Dobyns WB, Ledbetter DH (1997) A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Hum Mol Genet 6:147–155

  2. Endris V, Wogatzky B, Leimer U, Bartsch D, Zatyka M, Latif F, Maher ER, Tariverdian G, Kirsch S, Karch D, Rappold GA (2002) The novel Rho-GTPase activating gene MEGAP/srGAP3 has a putative role in severe mental retardation. Proc Natl Acad Sci USA 99:11754–11759

  3. Frangiskakis JM, Ewart AK, Morris CA, Mervis CB, Bertrand J, Robinson BF, Klein BP, Ensing GJ, Everett LA, Green ED, Proschel C, Gutowski NJ, Noble M, Atkinson DL, Odelberg SJ, Keating MT (1996) LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86:59–69

  4. Grammatico P, de Sanctis S, di Rosa C, Cupilari F, del Porto G (1994) First case of deletion 14q11.2q13: clinical phenotype. Ann Genet 37:30–32

  5. Hanashima C, Shen L, Li SC, Lai E (2002) Brain factor-1 controls the proliferation and differentiation of neocortical progenitor cells through independent mechanisms. J Neurosci 22:6526–6536

  6. Hanashima C, Li SC, Shen L, Lai E, Fishell G (2004) Foxg1 suppresses early cortical cell fate. Science 303:56–59

  7. Kamnasaran D, O‘Brien PC, Schuffenhauer S, Quarrell O, Lupski JR, Grammatico P, Ferguson-Smith MA, Cox DW (2001) Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients using flow-sorted chromosomes. Am J Med Genet 102:173–182

  8. Murphy DB, Wiese S, Burfeind P, Schmundt D, Mattei MG, Schulz-Schaeffer W, Thies U (1994) Human brain factor 1, a new member of the fork head gene family. Genomics 21:551–557

  9. Ramakers GJ (2002) Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci 25:191–199

  10. Ramelli GP, Remonda L, Lovblad KO, Hirsiger H, Moser H (2000) Abnormal myelination in a patient with deletion 14q11.2q13.1. Pediatr Neurol 23:170–172

  11. Schuffenhauer S, Leifheit HJ, Lichtner P, Peters H, Murken J, Emmerich P (1999) De novo deletion (14)(q11.2q13) including PAX9: clinical and molecular findings. J Med Genet 36:233–236

  12. Siebert PD, Chenchik A, Kellogg DE, Lukyanov KA, Lukyanov SA (1995) An improved PCR method for walking in uncloned genomic DNA. Nucleic Acids Res 23:1087–1088

  13. Stevenson RE, Schwartz CE, Schroer RJ (2000) X-Linked Mental Retardation. Oxford University Press, New York

  14. Su PH, Chen SJ, Lee IC, Wang KL, Chen JY, Hung HM, Lee CF (2004) Interstitial deletion of chromosome 14q in a Taiwanese infant with microcephaly. J Formos Med Assoc 103:385–387

  15. Warburton D (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49:995–1013

  16. Wirth J, Nothwang HG, van der Maarel S, Menzel C, Borck G, Lopez-Pajares I, Brondum-Nielsen K, Tommerup N, Bugge M, Ropers HH, Haaf T (1999) Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes. J Med Genet 36:271–278

  17. Xuan S, Baptista CA, Balas G, Tao W, Soares VC, Lai E (1995) Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres. Neuron 14:1141–1152

Download references


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.

Author information

Correspondence to Vera M. Kalscheuer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation


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