title: Mutations in MED12 cause X-linked Ohdo syndrome.
abstract: 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.
authors: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors: Anneke T
authors: AT
authors: Vulto-van Silfhout
authors: Bert B A
authors: BB
authors: de Vries
authors: Bregje W M
authors: BW
authors: van Bon
authors: Alexander
authors: A
authors: Hoischen
authors: Martina
authors: M
authors: Ruiterkamp-Versteeg
authors: Christian
authors: C
authors: Gilissen
authors: Fangjian
authors: F
authors: Gao
authors: Marloes
authors: M
authors: van Zwam
authors: Cornelis L
authors: CL
authors: Harteveld
authors: Anthonie J
authors: AJ
authors: van Essen
authors: Ben C J
authors: BC
authors: Hamel
authors: Tjitske
authors: T
authors: Kleefstra
authors: Michèl A A P
authors: MA
authors: Willemsen
authors: Helger G
authors: HG
authors: Yntema
authors: Hans
authors: H
authors: van Bokhoven
authors: Han G
authors: HG
authors: Brunner
authors: Thomas G
authors: TG
authors: Boyer
authors: Arjan P M
authors: AP
authors: de Brouwer
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D016569:Blepharophimosis / Q000235:genetics*; D001763:Blepharoptosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D059472:Exome; D050172:Genes, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: C460107:MED12 protein, human; D056892:Mediator Complex
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