A novel MED12 mutation: Evidence for a fourth phenotype.
Mutations of the MED12 gene have been reported mainly in males with FG (Opitz-Kaveggia), Lujan-Fryns, or X-linked Ohdo syndromes. Recently, a different phenotype characterized by minor anomalies, severe intellectual disability (ID), and absent language was reported in female and male patients belonging to the same family and carrying a frameshift MED12 mutation (c.5898dupC). Here, we report on two brothers and their niece affected by severe and mild ID, respectively, where whole exome sequencing combined with variant analysis within a panel of ID-related genes, disclosed a novel c.2312T>C (p.Ile771Thr) MED12 mutation. This variant, which has not been reported as a polymorphism, was not present in a third unaffected brother, and was predicted to be deleterious by five bioinformatic databases. This finding together with the phenotypic analogies shared with the carriers of c.5898dupC mutation suggests the existence of a fourth MED12-related disorder, characterized by severe ID, absent or deficient language and, milder, clinical manifestation in heterozygotes. We have reviewed the literature on MED12 heterozygotes, their clinical manifestations, and discuss the possible biological causes of this condition. © 2016 Wiley Periodicals, Inc.
Medical Genetics Unit, Hospital "Santa Maria della Misericordia", Perugia, Italy.
Paolo
P
Prontera
Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
Valentina
V
Ottaviani
Medical Genetics Unit, Hospital "Santa Maria della Misericordia", Perugia, Italy.
Daniela
D
Rogaia
Medical Genetics Unit, Hospital "Santa Maria della Misericordia", Perugia, Italy.
Ilenia
I
Isidori
Medical Genetics Unit, Hospital "Santa Maria della Misericordia", Perugia, Italy.
Amedea
A
Mencarelli
Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
Natascia
N
Malerba
Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.|Ph.D. Program in Experimental and Regenerative Medicine, University of Foggia, Foggia, Italy.
Dario
D
Cocciadiferro
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Pfundt
P
Rolph
Medical Genetics Unit, Hospital "Santa Maria della Misericordia", Perugia, Italy.
Gabriela
G
Stangoni
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Anneke
A
Vulto-van Silfhout
Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
Giuseppe
G
Merla
D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D055028:Comparative Genomic Hybridization; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype
C460107:MED12 protein, human; D056892:Mediator Complex
Lujan-Fryns syndrome; MED12; Ohdo syndrome; Opitz-Kaveggia syndrome; c.2312T>C; heterozygote penetrance; severe intellectual disability