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.