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Genotype-phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype

Gordon-Smith, Katherine, Green, Elaine, Grozeva, Detelina ORCID:, Tavadia, Sherine, Craddock, Nick ORCID: and Jones, Lisa 2018. Genotype-phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 177 (8) , pp. 717-726. 10.1002/ajmg.b.32679

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Darier disease (DD) is an autosomal dominant skin disorder caused by mutations in ATP2A2 encoding the sarco/endoplasmic reticulum Ca2+ ATPase Isoform 2 (SERCA2). Evidence of a population‐level association between DD and psychiatric disorders suggests that mutations in ATP2A2 may have pleiotropic effects on the brain as well as skin. Evidence of genotype–phenotype relationships between ATP2A2 mutations and neuropsychiatric phenotypes would further support this suggestion. We investigated genotype–phenotype correlations between lifetime neuropsychiatric features and ATP2A2 mutation type (dichotomized into likely gene disrupting [LGD] or protein altering) in 75 unrelated individuals with DD. We also looked for evidence of clustering of mutations within SERCA2 according to neuropsychiatric features. Combining our data with the existing literature, the rate of LGD mutations was found to be significantly higher among DD cases/families with bipolar disorder, schizophrenia, or affective psychosis (p = .011). We also found a significant relationship between mutations located in the S4–M4 region of the protein and the presence of a severe neuropsychiatric phenotype (p = .032). Our findings add support to the hypothesis that Darier‐causing mutations in ATP2A2 confer susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness. This, together with evidence from research on common polymorphisms confirms ATP2A2 as a gene at which variation influences susceptibility to major psychiatric illness.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Wiley-Blackwell
ISSN: 1552-4841
Date of First Compliant Deposit: 20 November 2018
Date of Acceptance: 1 August 2018
Last Modified: 14 Nov 2023 01:23

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