Homozygous silencing of the T-box transcription factor TBR2/EOMES locus results in a microcephaly syndrome with polymicrogyria and corpus callosum agenesis.

Homozygous silencing of the T-box transcription factor TBR2/EOMES locus results in a microcephaly syndrome with polymicrogyria and corpus callosum agenesis. L. Baala^{1, 2}, S. Briault³, H.C. Etchevers², F. Laumonnier³, A. Natiq¹, J. Amiel², N. Boddaert⁴, C. Picard⁵, A. Sbiti¹, A. Asermouh⁶, T. Attié-Bitach^{2, 7}, F. Encha-Razavi^{2, 7}, A. Munnich^{2, 7}, A. Sefiani¹, S. Lyonnet^{2, 7} 1) Département de génétique médicale, INH Rabat, Morocco; 2) Genetique INSERM U781, Hosp Necker, Paris 15, France; 3) INSERM U-619 Faculté de Médecine, Tours, France; 4) Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades (AP-HP), Paris, France; 5) Centre détude des Déficits Immunitaires, Hôpital Necker-Enfants Malades (AP-HP), Paris, France; 6) Hôpital dEnfants Avicenne, Rabat, Maroc; 7) Université René Descartes - Paris 5, Paris, France.

Mechanisms regulating brain size during neurogenesis include the regulation of neural progenitor proliferation and migration. We report a large consanguineous Moroccan family with a marked prenatal-onset microcephaly (mean occipito-frontal circumference at birth -4 SD) and severe motor delay with hypotonia in 4 affected children. Early lethality was observed in 3 children (death at 15-18 months of age), due to respiratory distress following chronic infections. The surviving child has had a persistent fever since birth. Recurrent infections have been noted. This autosomal recessive microcephaly syndrome was co-segregating with a homozygous balanced translocation between chromosomes 3p and 10q. The translocation was found at the homozygous status in all affected individuals (46,XY,t(3;10)(p24;q23)2x), while unaffected parents were heterozygous. We established a fine physical mapping and cloned the breakpoints on 3p24 and 10q23. Interestingly, neither of the two translocation breakpoints disrupted a known or predicted gene coding sequence. However, we showed that a position effect at the breakpoint on chromosome 3 silences the Tbox-brain2/Eomesodermin (TBR2/EOMES) transcript. Together with its expression pattern in the developing human brain, our data suggest an involvement of TBR2/EOMES in neuronal division and/or migration. Thus, mutations in not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.