Mutations in MED12 Cause X-Linked Ohdo Syndrome

• Published in: American journal of human genetics Vol. 92; no. 3; pp. 401 - 406
• Main Authors: Vulto-van Silfhout, Anneke T., de Vries, Bert B.A., van Bon, Bregje W.M., Hoischen, Alexander, Ruiterkamp-Versteeg, Martina, Gilissen, Christian, Gao, Fangjian, van Zwam, Marloes, Harteveld, Cornelis L., van Essen, Anthonie J., Hamel, Ben C.J., Kleefstra, Tjitske, Willemsen, Michèl A.A.P., Yntema, Helger G., van Bokhoven, Hans, Brunner, Han G., Boyer, Thomas G., de Brouwer, Arjan P.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2013; Cell Press; Elsevier
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Blepharophimosis; Blepharophimosis - genetics; Blepharoptosis - genetics; Child; Child, Preschool; Chromatin; Exome; Genes, X-Linked - genetics; Genetic Predisposition to Disease; Genotype & phenotype; Geriatrics; Heart Defects, Congenital - genetics; Humans; Infant; Infant, Newborn; Intellectual Disability - genetics; Learning disabilities; Male; Mediator Complex - genetics; Mental retardation; Missense mutation; Mutation; Mutation, Missense; Pathogenesis; Phenotype; Sequence Analysis, DNA - methods; X chromosome
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2013.01.007

Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.