title: Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects.
abstract: BACKGROUND
  Darier disease (DD) is a rare genodermatosis caused by heterozygous mutations in the ATP2A2 gene. It has been associated with neuropsychiatric manifestations.
  
  
  OBJECTIVE
  To investigate the genetic basis of Israeli patients with DD, and its association with the neuropsychiatric phenotype.
  
  
  METHODS
  A cohort of 32 families comprising 74 affected individuals and 13 unaffected family members was recruited from the Haemek Dermatology Department and other dermatology clinics in Israel. The individuals were evaluated by detailed questionnaires, physical examination and genetic analysis. The main outcome measures were genetic mutations, psychiatric profile and their association.
  
  
  RESULTS
  Twenty-three mutations in ATP2A2 were scattered over the entire gene, 14 of them novel. Two families shared the same mutation. Twenty-one patients (28%) had a history of psychiatric disorders, most of them mood disorders. Another seven patients (9%) were highly suspected of having a psychiatric disorder; 21 (28%) reported suicidal thoughts and five (7%) had attempted suicide. The psychiatric phenotype demonstrated inter- and intrafamilial variability, and was not associated with disease severity, family history of psychiatric disease or mutation location.
  
  
  CONCLUSIONS
  The cohort demonstrated genetic heterogeneity with no mutation cluster along the gene, and a high prevalence of psychiatric disorders. Although no clear genotype-phenotype correlation was found, the results point to a major effect of genetic background on psychiatric phenotype, together with other modifiers.
authors.affiliation: Department of Dermatology, Haemek Medical Center, Afula, Israel.|Division of Dermatology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.|The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: R P
authors.initials: RP
authors.lastname: Dodiuk-Gad
authors.affiliation: Department of Dermatology, Haemek Medical Center, Afula, Israel.|The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Cohen-Barak
authors.affiliation: The Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Genetic Institute, Haemek Medical Center, Afula, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Khayat
authors.affiliation: Genetic Institute, Haemek Medical Center, Afula, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Milo
authors.affiliation: Genetic Institute, Haemek Medical Center, Afula, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Amariglio-Diskin
authors.affiliation: The Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Genetic Institute, Haemek Medical Center, Afula, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Danial-Faran
authors.affiliation: Department of Dermatology, Haemek Medical Center, Afula, Israel.|The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Sah
authors.affiliation: Department of Dermatology, Haemek Medical Center, Afula, Israel.|The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Ziv
authors.affiliation: Department of Dermatology, Haemek Medical Center, Afula, Israel.|The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Shani-Adir
authors.affiliation: Department of Dermatology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Amichai
authors.affiliation: Department of Dermatology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Zlotogorski
authors.affiliation: The Rappaport Faculty of Medicine, Technion, Haifa, Israel.|The Simon Winter Institute for Human Genetics, Bnei-Zion Medical Center, Haifa, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Borochowitz
authors.affiliation: Department of Dermatology, Haemek Medical Center, Afula, Israel.|The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Rozenman
authors.affiliation: The Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Genetic Institute, Haemek Medical Center, Afula, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Shalev
mesh_terms: D000328:Adult; D007644:Darier Disease / Q000208:ethnology / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007557:Israel / Q000208:ethnology; D008297:Male; D001523:Mental Disorders / Q000208:ethnology / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009460:Neurologic Examination; D010641:Phenotype; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human