title: A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring.
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.
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.forename: Laura
authors.initials: L
authors.lastname: Hildebrand
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.forename: Evelin
authors.initials: E
authors.lastname: Schrock
authors.forename: Diana
authors.initials: D
authors.lastname: Mitter
mesh_terms: D002675:Child, Preschool; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008297:Male; D017354:Point Mutation; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D022821:RNA Splice Sites; D012333:RNA, Messenger; C455847:EHMT1 protein, human; D011495:Histone-Lysine N-Methyltransferase