Article Text

Original research
Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank
  1. Lucija Brcic1,
  2. Jack FG Underwood2,3,
  3. Kimberley M Kendall2,
  4. Xavier Caseras2,
  5. George Kirov2,
  6. William Davies1,2,3
  1. 1 School of Psychology, Cardiff University, Cardiff, UK
  2. 2 MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
  3. 3 Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
  1. Correspondence to Dr William Davies, School of Psychology, Tower Building, 70, Park Place, Cardiff University, Cardiff, CF10 3AT, UK; daviesw4{at}


Background X-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions spanning STS. Some medical comorbidities have been identified in XLI cases, but small samples of relatively young patients has limited this. STS is highly expressed in subcortical brain structures, and males with XLI and female deletion carriers appear at increased risk of developmental/mood disorders and associated traits; the neurocognitive basis of these findings has not been examined.

Methods Using the UK Biobank resource, comprising participants aged 40–69 years recruited from the general UK population, we compared multiple medical/neurobehavioural phenotypes in males (n=86) and females (n=312) carrying genetic deletions spanning STS (0.8–2.5 Mb) (cases) to male (n=190 577) and female (n=227 862) non-carrier controls.

Results We identified an elevated rate of atrial fibrillation/flutter in male deletion carriers (10.5% vs 2.7% in male controls, Benjamini-Hochberg corrected p=0.009), and increased rates of mental distress (p=0.003), irritability (p<0.001) and depressive-anxiety traits (p<0.05) in male deletion carriers relative to male controls completing the Mental Health Questionnaire. While academic attainment was unaffected, male and female deletion carriers exhibited impaired performance on the Fluid Intelligence Test (Cohen’s d≤0.05, corrected p<0.1). Neuroanatomical analysis in female deletion carriers indicated reduced right putamen and left nucleus accumbens volumes (Cohen’s d≤0.26, corrected p<0.1).

Conclusion Adult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems; altered basal ganglia structure may underlie altered function and XLI-associated psychiatric/behavioural phenotypes. These results provide information for genetic counselling of deletion-carrying individuals and reinforce the need for multidisciplinary medical care.

  • arrhythmias
  • copy-number
  • dermatology
  • psychiatry
  • neurosciences

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  • Twitter @JFGUnderwood, @DrKKendall, @GeorgeKirov1, @DrWillDavies77

  • Correction notice This article has been corrected since it was published Online First. A minor error in reporting the number of female control subjects in the main text has been corrected. The error does not change any of the analyses or conclusions of the paper.

  • Contributors LB, KMK and XC analysed the data; JFGU and GK called the CNVs; WD conceived the project, drafted the manuscript and took part in all analysis steps; all authors edited the draft manuscript. WD is responsible for the overall content of the manuscript.

  • Funding LB was funded by the Cardiff University School of Psychology Research Internship (SPRInt) Programme. JFGU was funded by a Wellcome Trust GW4-CAT Clinical Research Fellowship and is supported via Welsh Clinical Academic Track funded by Health Education and Improvement Wales. KMK was funded by a Wellcome Trust Clinical Research Fellowship (201171/Z/16/Z). The work was conducted within the Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (Centre Grant Number MR/L010305/1).

  • Disclaimer The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Ethical approval for the study was granted by the North West multicentre ethics committee, UK under Research Ethics Committee approval number 11/NW/0382.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data may be obtained from a third party and are not publicly available. All CNV calls will be made available to the UK Biobank, in accordance with their requirements. Genetic and phenotypic data may be accessed through application to the UK Biobank (

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