Researchers have uncovered a novel neurodevelopmental disorder featuring multiple congenital anomalies that is linked to variants in the MED16 gene. Published in the American Journal of Human Genetics, the study identified causative biallelic MED16 variants in 25 patients presenting with an autosomal recessive syndrome marked by intellectual disability, motor delay and a range of malformations. These malformations appeared in various combinations, predominantly affecting the face and skull, heart and limbs in most patients. The researchers conclude that certain tissues are more sensitive to loss of MED16 function.

MED16 encodes a key subunit within the Mediator complex’s tail module. This multiprotein complex is essential in gene transcription, connecting transcription factors and RNA polymerase II and promoting the assembly of the preinitiation complex, a necessary step for initiating transcription. MED16 interacts with several other components of the Mediator tail module, as well as with MED14, which acts as a structural backbone for the complex.

Unlike several other Mediator complex subunits, MED16 variants have so far not been linked to a human disorder. This study is thus the first to implicate MED16 within the framework of a group of neurodevelopmental and neurodegenerative disorders that arise from defects in Mediator complex components, referred to as MEDopathies.