title: Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.
abstract: BACKGROUND
  The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far.
  
  
  RESULTS
  By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein.
  
  
  CONCLUSIONS
  The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. t.kleefstra@antrg.umcn.nl
authors.forename: T
authors.initials: T
authors.lastname: Kleefstra
authors.forename: W A
authors.initials: WA
authors.lastname: van Zelst-Stams
authors.forename: W M
authors.initials: WM
authors.lastname: Nillesen
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: G
authors.initials: G
authors.lastname: Houge
authors.forename: N
authors.initials: N
authors.lastname: Foulds
authors.forename: M
authors.initials: M
authors.lastname: van Dooren
authors.forename: M H
authors.initials: MH
authors.lastname: Willemsen
authors.forename: R
authors.initials: R
authors.lastname: Pfundt
authors.forename: A
authors.initials: A
authors.lastname: Turner
authors.forename: M
authors.initials: M
authors.lastname: Wilson
authors.forename: J
authors.initials: J
authors.lastname: McGaughran
authors.forename: A
authors.initials: A
authors.lastname: Rauch
authors.forename: M
authors.initials: M
authors.lastname: Zenker
authors.forename: M P
authors.initials: MP
authors.lastname: Adam
authors.forename: M
authors.initials: M
authors.lastname: Innes
authors.forename: C
authors.initials: C
authors.lastname: Davies
authors.forename: A González-Meneses
authors.initials: AG
authors.lastname: López
authors.forename: R
authors.initials: R
authors.lastname: Casalone
authors.forename: A
authors.initials: A
authors.lastname: Weber
authors.forename: L A
authors.initials: LA
authors.lastname: Brueton
authors.forename: A Delicado
authors.initials: AD
authors.lastname: Navarro
authors.forename: M Palomares
authors.initials: MP
authors.lastname: Bralo
authors.forename: H
authors.initials: H
authors.lastname: Venselaar
authors.forename: S P A
authors.initials: SP
authors.lastname: Stegmann
authors.forename: H G
authors.initials: HG
authors.lastname: Yntema
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9; D005260:Female; D006238:Haploidy; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D016415:Sequence Alignment; D017384:Sequence Deletion; D013577:Syndrome; D016615:Telomere / Q000235:genetics*
chemical_list: C455847:EHMT1 protein, human; D011495:Histone-Lysine N-Methyltransferase