De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females
| Autor: | Charu Deshpande, Joke B. G. M. Verheij, H Van Bokhoven, Siddharth Banka, J. S. Klein Wassink-Ruiter, Elizabeth J. Bhoj, S. C. Huffels, R. Pfundt, Ernie M.H.F. Bongers, Anne Gregor, A.P.M. de Brouwer, André Reis, Christiane Zweier, Hakon Hakonarson, Nicola K. Ragge, L. Gompertz, Dong Li, Sanmati Cuddapah, Alexander P.A. Stegmann, Sally Ann Lynch, A.T. Vulto-van Silfhout, Willie Reardon, Gyri Aasland Gradek, Daniel L. Polla, Kate Chandler, C. T. R. M. Stumpel, B. B. A. de Vries, R. Wennekes, Elaine H. Zackai, Siren Berland, Erika Leenders, K. Hill-Karfe |
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| Přispěvatelé: | Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9) |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
FG syndrome Mutation Missense 030105 genetics & heredity Biology Short stature MED12 03 medical and health sciences Exon BLEPHAROPHIMOSIS Genes X-Linked Intellectual Disability medicine Missense mutation Humans Genetics(clinical) TRANSCRIPTION Gene MUTATION Genetics (clinical) Genetics OHDO SYNDROME Mediator Complex Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Syndrome medicine.disease Phenotype Blepharophimosis GENE DELINEATION FG SYNDROME 030104 developmental biology Neurodevelopmental Disorders Mental Retardation X-Linked Female medicine.symptom MENTAL-RETARDATION |
| Zdroj: | Genetics in Medicine, 23, 4, pp. 645-652 Polla, DL, Bhoj, EJ, Verheij, JBGM, Wassink-Ruiter, JSK, Reis, A, Deshpande, C, Gregor, A, Hill-Karfe, K, Silfhout, ATV, Pfundt, R, Bongers, EMHF, Hakonarson, H & de, B APM 2020, ' De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females ', Genetics in medicine : official journal of the American College of Medical Genetics . https://doi.org/10.1038/s41436-020-01040-6 Genetics in Medicine, 23(4), 645-652. Nature Publishing Group Genetics in Medicine, 23, 645-652 |
| ISSN: | 1098-3600 |
| DOI: | 10.1038/s41436-020-01040-6 |
| Popis: | Contains fulltext : 234992.pdf (Publisher’s version ) (Closed access) 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. |
| Databáze: | OpenAIRE |
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