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.
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.
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).
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.
Identifying the spectrum of biomedical traits in adults with pathogenic copy number variants (CNVs)
Deletions and duplications of large stretches of chromosomes, known as copy number variants (CNVs), cause several neurodevelopmental disorders, such as schizophrenia, developmental delay and autism spectrum disorder. However, the full clinical spectrum associated with most of these CNVs has not yet been established and there is limited evidence of the impact of these CNVs in the general population, e.g. in apparently healthy carriers. We propose to identify the carriers of pathogenic CNVs in the full UK Biobank sample. We will then identify the cognitive deficits and common medical problems that are increased in carriers of each of these CNVs. The rarity of most pathogenic CNVs has so far prevented researchers from confidently establishing their full medical and neurocognitive consequences. Therefore it is currently impossible for genetic counsellors to give accurate advice to CNV carriers. Our research will provide the most comprehensive assessment of neuropsychiatric and common medical problems associated with known pathogenic CNVs. This will result in a greater understanding of the risks conferred by these CNVs for the development of diseases, and give clinicians the necessary information for diagnosing, counselling and treating the carriers of these CNVs. We will first generate a set of high quality CNVs from all participants in the UK Biobank cohort using the data from microarray genotyping already conducted by Affymetrix. (If UK Biobank calls the CNVs centrally, we can use these calls and just apply our quality control filtering). We will identify the individuals carrying pathogenic CNVs. Carriers of pathogenic CNVs will then be compared with the remaining participants, who are free of such CNVs, for neuropsychiatric problems (including cognitive performance), common medical conditions, and basic characteristics (e.g. weight and height), which can be affected by CNVs. We require genetic data from the full UK Biobank cohort. We also need a set of basic demographic and common health outcomes that could be affected by CNVs. These include neuropsychiatric outcomes such as epilepsy, psychosis, mood disorders, cognitive tests, educational indices, and self-reported medical/psychiatric conditions. When it becomes available, we would like to add the diagnostic codes from the primary care data, to supplement the self-reports. Carriers of these CNVs might have an increased rate of premature terminations and have fewer children, therefore we also want to collect the self-reported information on these outcomes.
|Lead investigator:||Professor George Kirov|
|Lead institution:||Cardiff University|
2 related Returns
|Return ID||App ID||Description||Archive Date|
|783||14421||Cognitive performance among carriers of pathogenic copy number variants: Analysis of 152,000 UK Biobank subjects||17 Oct 2017|
|1701||14421||Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank||12 Aug 2019|
|3445||Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank||Brcic L et al.||2020||J Med Genet|