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Characterising heart rhythm abnormalities associated with Xp22.31 deletion

Wren, Georgina, Baker, Emily, Underwood, Jack ORCID:, Humby, Trevor ORCID:, Thompson, Andrew ORCID:, Kirov, George ORCID:, Escott-Price, Valentina ORCID: and Davies, William ORCID: 2023. Characterising heart rhythm abnormalities associated with Xp22.31 deletion. Journal of Medical Genetics 60 , pp. 636-643. 10.1136/jmg-2022-108862

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Background Genetic deletions at Xp22.31 are associated with the skin condition X linked ichthyosis (XLI), and with a substantially increased risk of atrial fibrillation/flutter (AF), in males. AF is associated with elevated thrombosis, heart failure, stroke and dementia risk. Methods Through: (a) examining deletion carriers with a diagnosis of AF in UK Biobank, (b) undertaking an online survey regarding abnormal heart rhythms (AHRs) in men/boys with XLI and female carriers of XLI-associated deletions and (c) screening for association between common genetic variants within Xp22.31 and idiopathic AF-related conditions in UK Biobank, we have investigated how AHRs manifest in deletion carriers, and have identified associated risk factors/comorbidities and candidate gene(s). Finally, we examined attitudes towards heart screening in deletion carriers. Results We show that AHRs may affect up to 35% of deletion carriers (compared with <20% of age-matched non-carriers), show no consistent pattern of onset but may be precipitated by stress, and typically resolve quickly and respond well to intervention. Gastrointestinal (GI) conditions and asthma/anaemia were the most strongly associated comorbidities in male and female deletion carriers with AHR, respectively. Genetic analysis indicated significant enrichment of common AF risk variants around STS (7 065 298–7 272 682 bp in GRCh37/hg19 genome build) in males, and of common GI disorder and asthma/anaemia risk variants around PNPLA4 (7 866 804–7 895 780 bp) in males and females, respectively. Deletion carriers were overwhelmingly in favour of cardiac screening implementation. Conclusion Our data suggest AHRs are frequently associated with Xp22.31 deletion, and highlight subgroups of deletion carriers that may be prioritised for screening. Examining cardiac function further in deletion carriers, and in model systems lacking steroid sulfatase, may clarify AF pathophysiology.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: BMJ Publishing Group
ISSN: 1468-6244
Funders: MRC, Wellcome Trust
Date of First Compliant Deposit: 16 November 2022
Date of Acceptance: 29 October 2022
Last Modified: 01 Oct 2023 09:00

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