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A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons50604

Tzschach,  Andreas
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institut für Humangenetik, Universitätsklinikum Tübingen;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50606

Ullmann,  Reinhard
Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Rump, A., Hildebrand, L., Tzschach, A., Ullmann, R., Schrock, E., & Mitter, D. (2012). A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. European journal of human genetics: EJHG; the official journal of the European Society of Human Genetics, 2012, e-e. doi:10.1038/ejhg.2012.267.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-EC84-6
Abstract
The euchromatic histone-lysine N-methyltransferase 1 (EHMT1) gene was examined in a 3-year-old boy with characteristic clinical features of Kleefstra syndrome. Sequencing of all 27 EHMT1 exons revealed a novel mutation, NM_024757.4:c.2712+1G>A, which affects the splice donor of intron 18. Whereas the index patient is heterozygous for that mutation, his phenotypically normal mother shows tissue-specific mosaicism. Sequencing of EHMT1 RT-PCR products revealed two aberrant transcript variants: in one variant, exon 18 was skipped; in the other, a near-by GT motif was used as splice donor and intronic sequence was inserted between exons 18 and 19. Both transcript variants were found in the patient and his mother. The latter had lower amounts of these transcripts consistent with mosaic status. This is the first description of an EHMT1 point mutation being inherited from a parent with verified mosaicism. The constitutive c.2712+1G>A splice site mutation in EHMT1 is fully pathogenic, and the transcript variants produced do not attenuate the severity of the disease.European Journal of Human Genetics advance online publication, 12 December 2012; doi:10.1038/ejhg.2012.267.