Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank

J Med Genet. 2020 Oct;57(10):692-698. doi: 10.1136/jmedgenet-2019-106676. Epub 2020 Mar 5.


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.

Keywords: arrhythmias; copy-number; dermatology; neurosciences; psychiatry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arrhythmias, Cardiac / complications
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / psychology
  • Biological Specimen Banks
  • Female
  • Gene Deletion
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Ichthyosis, X-Linked / complications
  • Ichthyosis, X-Linked / genetics*
  • Ichthyosis, X-Linked / pathology
  • Ichthyosis, X-Linked / psychology
  • Male
  • Mental Disorders / complications
  • Mental Disorders / genetics*
  • Mental Disorders / pathology
  • Mental Disorders / psychology
  • Middle Aged
  • Phenotype
  • Skin / pathology
  • Steryl-Sulfatase / genetics*
  • Surveys and Questionnaires
  • United Kingdom / epidemiology


  • Steryl-Sulfatase