The TBX1 gene in the 22q11.2 deletion and duplication syndromes: a susceptibility factor for mental retardation. D. Heine-Suner¹, L. Torres-Juan¹, J. Rosell¹, M. Morla³, F. Garcia-Algas², M. de la Fuente², M. Juan⁴, A. Tubau⁴, M. Bernues¹, A. Perez-Granero¹, N. Govea¹, X. Busquets³. 1) Secció de Genetica, Hosp Univ Son Dureta, Andrea Doria 55, Palma de Mallorca 07014, Balearic Islands, Spain; 2) Servei de Pediatría, Hosp Univ Son Dureta, Andrea Doria 55, Palma de Mallorca 07014, Balearic Islands, Spain; 3) Unitat de Investigació, Hosp Univ Son Dureta, Andrea Doria 55, Palma de Mallorca 07014, Balearic Islands, Spain; 4) Servei de Obstetricia i Ginecologia, Hospital Son Llatzer, Carretera de Manacor, km4, 07198 Palma de Mallorca, Balearic Islands, Spain.
   A mutational screen for TBX1 mutations was performed on 38 non-deleted patients that had clinical features compatible with the 22q11.2 deletion syndrome. Two rare variants were identified. The first is a de novo missense mutation in a patient with Tetralogy of Fallot, immunodeficiency and slight developmental delays. This mutation is localized in exon 9C and possibly affects a conserved amino acid within a transactivation domain. The second mutation is within the 5UTR region. This change affects two brothers with isolated congenital heart disease. Modelling studies show that this change affects the 5UT mRNA secondary structure. In addition, in vitro translation experiments showed this change to double the protein doses. Recently, patients referred for fragile-X were found to be carriers of duplications in the 22q11.2 region. Because the 5UT nucleotide change is functionally equivalent to a duplication of the TBX1 gene we screened 200 patients referred for fragile-X determination and detected 3 carriers of this change not detected in 400 healthy controls. However, affected carriers had all a normal carrier parent, which shows that the presence of the 5UT change is not sufficient to cause congenital heart disease or mental retardation. In conclusion, we report a new de novo mutation in the TBX1 gene responsible for cardiac defects as the main feature, and show that a rare variant affects TBX1 doses. Furthermore, we find that the change that increases the doses of TBX1 is a susceptibility factor to suffer features of the 22q11.2 duplication syndrome.