title: Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.
abstract: A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q-) syndrome has been estimated to be <1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1). Previous studies suggested that haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations--a nonsense mutation and a frameshift mutation--in the EHMT1 gene in patients with a typical 9q- phenotype. These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome.
authors.affiliation: Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. T.Kleefstra@antrg.umcn.nl
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Astrid R
authors.initials: AR
authors.lastname: Oudakker
authors.forename: Willy M
authors.initials: WM
authors.lastname: Nillesen
authors.forename: Alex
authors.initials: A
authors.lastname: Magee
authors.forename: David
authors.initials: D
authors.lastname: Geneviève
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Hilde
authors.initials: H
authors.lastname: van Esch
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Ben C J
authors.initials: BC
authors.lastname: Hamel
authors.forename: Erik A
authors.initials: EA
authors.lastname: Sistermans
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D013577:Syndrome
chemical_list: C455847:EHMT1 protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase