A new MEDopathy caused by biallelic mutations of MED16

Published on

Members of the former “Embryology and Genetics of Malformations” laboratory at Institut Imagine have sequenced the genome of a brother and sister with an undiagnosed acrofacialdysostosis (craniofacial and limb malformations) and intellectual disability. The team identified variants of the MED16 gene. This gene encodes a subunit of the Mediator multiprotein complex, which regulates the transcription of DNA into RNA. By sharing genomic data, the researchers identified a cohort of 25 individuals carrying biallelic variants of MED16 and confirmed the causality of this gene. The results, recently published in the American Journal of Human Genetics, show the impact of missense variants on protein conformation and cellular localization. Finally, by invalidating this gene in zebrafish, they observed a growth defect and early death of larval fish, confirming the essential role of med16 in development. This study thus describes a new MEDopathy and the major role of the MED16 gene in craniofacial, limb, heart and central nervous system development.

The sequencing of the genomes of a brother and sister with several developmental anomalies (growth retardation, motor retardation, intellectual disability and cardiac, limb and craniofacial malformations) identified a biallelic mutation (on both chromosomes) in the MED16 gene. This gene encodes a subunit of the Mediator complex, a multi-protein complex that regulates transcription, the first stage of gene expression during which DNA is “copied” into RNA. Pathogenic variants of other Mediator subunits, already identified in human diseases, generally lead to neurodevelopmental or neurodegenerative disorders that may be associated with malformations of other organs, and are grouped together under the term MEDopathies. A new study by the former “Embryology and Genetics of Malformations” laboratory at the Institut Imagine has described a novel rare congenital malformation syndrome: acrofacialdysostosis (craniofacial and limb malformation) with intellectual disability, resulting from biallelic mutations in the MED16 gene.

Using the GeneMatcher database, the team was able to identify a further 23 individuals from 17 families with biallelic MED16 mutations. This cohort of 25 individuals is reported by Charlotte Guillouet, a PhD student under the supervision of Chris Gordon and Jeanne Amiel in the “Embryology and Genetics of Malformations” laboratory at the Institut Imagine (Inserm, AP-HP, Université Paris Cité). In silico (computer simulation) and in vitro (test tube, laboratory) studies validated the pathogenicity of the vast majority of the MED16 variants.

Finally, two zebrafish lines in which the med16 gene is “switched off” show stunted growth and early mortality compared with “normal” fish or fish carrying the mutation on a single chromosome, thus confirming the important role of med16 during development.

This study, recently published in the American Journal of Human Genetics, describes a novel, rare autosomal recessive MEDopathy syndrome (the mutation must be present on both chromosomes for the disease to appear). It also confirms the importance of optimal functioning of the Mediator complex for brain development, and suggests a more specific role for certain subunits during development.

Reference : 
Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations 
C Guillouet et al., Am J Hum Genet, 2025 
Corresponding authors : Charlotte Guillouet, Jeanne Amiel and Chris Gordon 
DOI : 10.1016/j.ajhg.2025.02.016