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.
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References
Kleefstra T, Smidt M, Banning MJ et al: Disruption of the gene euchromatin histone methyl transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. J Med Genet 2005; 42: 299–306.
Kleefstra T, Brunner HG, Amiel J et al: Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 2006; 79: 370–377.
Willemsen MH, Vulto-van Silfhout AT, Nillesen WM et al: Update on Kleefstra Syndrome. Mol Syndromol 2012; 2: 202–212.
Willemsen MH, Beunders G, Callaghan M et al: Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. Clin Genet 2011; 80: 31–38.
Yatsenko SA, Brundage EK, Roney EK, Cheung SW, Chinault AC, Lupski JR : Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum Mol Genet 2009; 18: 1924–1936.
Kleefstra T, van Zelst-Stams WA, Nillesen WM et al: Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 2009; 46: 598–606.
Kleefstra T, Nillesen WM, Yntema HG : Kleefstra syndrome; in Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds): GeneReviews. Seattle, WA: University of Washington, Seattle, 1993, 2010/10/15 (edn).
Seabright M : Human chromosome banding. Lancet 1972; 1: 967.
Collins RE, Northrop JP, Horton JR et al: The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. Nat Struct Mol Biol 2008; 15: 245–250.
Steinbusch C, van Roozendaal K, Tserpelis D et al: Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome. Clin Genet 2012.
Acknowledgements
We thank the patient and his family for their cooperation and the cooperating physicians for referral of the patient, especially Lothar Bergmann (Universitätskinderklinik Leipzig). We thank Professor Eberhard Passarge and the Executive Board of the University of Leipzig Hospitals and Clinics for continuous support. Array CGH analysis was performed at the Max-Planck-Institute of Molecular Genetics Berlin, member of the ‘German Mental Retardation Network’ (MRNET), funded by the German Federal Ministry of Education and Research (BMBF) as part of the National Genome Research Network (NGFNplus/www.ngfn.de/englisch/15.htm, project reference numbers 01GS08164, 01GS08167).
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Rump, A., Hildebrand, L., Tzschach, A. et al. A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. Eur J Hum Genet 21, 887–890 (2013). https://doi.org/10.1038/ejhg.2012.267
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DOI: https://doi.org/10.1038/ejhg.2012.267
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