MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Abstract

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

MED12 Mutation in Two Families with X-Linked Ohdo Syndrome

“…In these individuals, nonsense and frameshift variants were identified in addition to the missense variants described in the well-known aforementioned conditions. The missense variants that cause disease in males and females were not clustered in one specific protein domain or motif and can cause different severity of (neuro)developmental disease in males and females [ 11 ]. In addition, truncating variants described in females and two males with divergent phenotypes are not related to a specific position in the MED12 protein.…”

“…In addition, truncating variants described in females and two males with divergent phenotypes are not related to a specific position in the MED12 protein. This suggests that it is not the position of the variant that determines phenotype, but rather the effect of the variant on MED12 activity [ 11 ].…”

“…To date, 77 MED12 variants have been described, in part due to the introduction of next generation sequencing techniques (NGS) [ 11 ]. Interestingly, only 8 of the 77 are associated with the XLID syndromes described above.…”

Role of the Mediator Complex and MicroRNAs in Breast Cancer Etiology

“…MED12 is an extensively studied subunit of the mediator complex kinase module. Its link with numerous illnesses has attracted much attention [ 64 , 65 , 66 ]. MED12 changes in its sequence and expression may be harmful to cells, ultimately manifesting into different disease characteristics [ 67 ].…”

“…MED12 changes in its sequence and expression may be harmful to cells, ultimately manifesting into different disease characteristics [ 67 ]. The MED12 gene is found on chromosome X, at location Xq13.1 encompassing a 25-kb area with 45 exons and coding for 230-kDa protein 2.177 amino acids long [ 64 , 65 , 66 ] ( Figure 4 B). It is part of the kinase module that consists of MED12, MED13, Cyclin C (CCNC) and cyclin-dependent kinase 8 (CDK8) [ 68 ] ( Figure 3 ).…”