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  The power of the Mediator complex—Expanding the genetic architecture and phenotypic spectrum of MED12‐related disorders

Charzewska, A., Maiwald, R., Kahrizi, K., Oehl‐Jaschkowitz, B., Dufke, A., Lemke, J. R., et al. (2018). The power of the Mediator complex—Expanding the genetic architecture and phenotypic spectrum of MED12‐related disorders. Clinical Genetics: an international journal of genetics in medicine, 2018: 13412. doi:10.1111/cge.13412.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-105F-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-1060-F
Genre: Journal Article

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 Creators:
Charzewska, A., Author
Maiwald, R., Author
Kahrizi, K., Author
Oehl‐Jaschkowitz, B., Author
Dufke, A., Author
Lemke, J. R., Author
Enders, H., Author
Najmabadi, H., Author
Tzschach, A., Author
Hachmann, W., Author
Jensen, C., Author
Bienek, M., Author
Poznański, J., Author
Nawara, M., Author
Chilarska, T., Author
Obersztyn, E., Author
Hoffman‐Zacharska, D., Author
Gos, M., Author
Bal, J., Author
Kalscheuer, V. M.1, Author              
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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Free keywords: FG syndrome; Lujan-Fryns syndrome; MED12; Ohdo syndrome; X-linked intellectual disability; molecular modeling
 Abstract: MED12 is a member of the large Mediator complex that controls cell growth, development, and differentiation. Mutations in MED12 disrupt neuronal gene expression and lead to at least three distinct X-linked intellectual disability syndromes (FG, Lujan-Fryns, and Ohdo). Here, we describe six families with missense variants in MED12 (p.(Arg815Gln), p.(Val954Gly), p.(Glu1091Lys), p.(Arg1295Cys), p.(Pro1371Ser), and p.(Arg1148His), the latter being first reported in affected females) associated with a continuum of symptoms rather than distinct syndromes. The variants expanded the genetic architecture and phenotypic spectrum of MED12-related disorders. New clinical symptoms included brachycephaly, anteverted nares, bulbous nasal tip, prognathism, deep set eyes, and single palmar crease. We showed that MED12 variants, initially implicated in X-linked recessive disorders in males, may predict a potential risk for phenotypic expression in females, with no correlation of the X chromosome inactivation pattern in blood cells. Molecular modeling (Yasara Structure) performed to model the functional effects of the variants strongly supported the pathogenic character of the variants examined. We showed that molecular modeling is a useful method for in silico testing of the potential functional effects of MED12 variants and thus can be a valuable addition to the interpretation of the clinical and genetic findings.

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Language(s): eng - English
 Dates: 2018-07-032018-07-13
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1111/cge.13412
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Title: Clinical Genetics: an international journal of genetics in medicine
  Other : Clin. Genet.
Source Genre: Journal
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Publ. Info: Copenhagen : Munksgaard.
Pages: - Volume / Issue: 2018 Sequence Number: 13412 Start / End Page: - Identifier: ISSN: 0009-9163
CoNE: /journals/resource/954925391292