Three novel mutations in MED12 cause Ohdo syndrome Maat-Kievit-Brunner type. A. T. Vulto-van Silfhout1, A. Hoischen1, B. W. M. van Bon1, W. M. Nillesen1, C. Gilissen1, F. Gao2, J. M. Spaeth2, B. C. Hamel1, T. Kleefstra1, M. A. A. P. Willemsen3, H. van Bokhoven1, H. G. Yntema1, B. B. A. de Vries1, H. G. Brunner1, T. G. Boyer2, A. P. M. de Brouwer1 1) Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; 2) Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center, San Antonio, USA; 3) Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

   Ohdo syndrome [MIM 249620] is characterized by intellectual disability and typical facial features including blepharophimosis. Clinically the blepharophimosis-intellectual disability syndromes have been classified in five distinct subgroups: del(3)(pter) type, Ohdo type, Say-Barber-Biesecker-Young-Simpson (SBBYS) type, Verloes type, and Maat-Kievit-Brunner (MKB) type. Here, we performed exome sequencing in two families with two affected males with Ohdo syndrome MKB type, which is characterized by X-linked inheritance and facial coarsening at older age. Two novel missense mutations were identified in Mediator of RNA polymerase II transcription subunit 12 (MED12; NM_005120.2), p.(Arg1148His) and p.(Ser1165Pro), that segregated with the disease phenotype. Upon subsequent analysis of an additional cohort of nine single male patients with Ohdo syndrome, we detected one additional de novo missense change in MED12: p.(His1729Asn). This patient also presented with the clinical hallmarks of Ohdo syndrome MKB type. Previously, three other specific missense mutations in MED12 have been described in patients with FG syndrome and Lujan-Fryns syndrome. Our patients clearly differ from these two syndromes as they have the classical Ohdo features ptosis and blepharophimosis, while the tall forehead, macrocephaly, and broad thumbs and halluces as seen in Lujan-Fryns and FG syndrome and the typical small ears and hair whorls as seen in FG syndrome are less apparent. However, in adulthood the facial appearance of Ohdo patients type MKB becomes more coarse, and the distinction between these syndromes becomes less apparent. The occurrence of three different hemizygous missense mutations in three unrelated families with Ohdo syndrome MKB type, shows that MED12 is the causative gene for this Ohdo syndrome subtype. The identification of an X chromosomal gene in Ohdo syndrome has important implications for the recurrence risk in the families.

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