Journal Article

De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females


Purpose. MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. Methods. By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. Results. Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. Conclusion. We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

Attached files


Polla, DL
Bhoj, EJ
Verheij, JBGM
Klein Wassink-Ruiter, JS
Reis, A
Deshpande, C
Gregor, A
Hill-Karfe, K
Vulto-van Silfhout, AT
Pfundt, R
Bongers, EMHF
Hakonarson, H
Berland, S
Gradek, G
Banka, S
Chandler, K
Gompertz, L
Huffels, SC
Stumpel, CTRM
Wennekes, R
Stegmann, APA
Reardon, W
Leenders, EKSM
de Vries, BBA
Li D
Zackai, E
Ragge, Nicole
Lynch, SA
Cuddapah, S
van Bokhoven, H
Zweier, C
de Brouwer, APM

Oxford Brookes departments

Department of Biological and Medical Sciences


Year of publication: 2020
Date of RADAR deposit: 2020-12-16

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This RADAR resource is the Accepted Manuscript of De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females


  • Owner: Joseph Ripp
  • Collection: Outputs
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