title: Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability.
abstract: BACKGROUND
  Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes.
  
  
  RESULTS
  We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1-4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1-3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1-3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.
  
  
  CONCLUSIONS
  Patients carrying JARID2 deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of ATXN1 seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.
authors.affiliation: Department of Medical Genetics, University of Oslo, P,O, Box 1036, Blindern, Oslo N-0315, Norway.
authors.forename: Tuva
authors.initials: T
authors.lastname: Barøy
authors.forename: Doriana
authors.initials: D
authors.lastname: Misceo
authors.forename: Petter
authors.initials: P
authors.lastname: Strømme
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Holmgren
authors.forename: Olaug Kristin
authors.initials: OK
authors.lastname: Rødningen
authors.forename: Anne
authors.initials: A
authors.lastname: Blomhoff
authors.forename: Johan Robert
authors.initials: JR
authors.lastname: Helle
authors.forename: Alice
authors.initials: A
authors.lastname: Stormyr
authors.forename: Bjørn
authors.initials: B
authors.lastname: Tvedt
authors.forename: Madeleine
authors.initials: M
authors.lastname: Fannemel
authors.forename: Eirik
authors.initials: E
authors.lastname: Frengen
mesh_terms: D000293:Adolescent; D000067696:Ataxin-1; D000067528:Ataxins; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6; D055028:Comparative Genomic Hybridization; D005260:Female; D005684:Gait; D057895:Haploinsufficiency; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D006657:Histones; C547777:JARID2 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2