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. 2023 Jul;60(7):636-643.
doi: 10.1136/jmg-2022-108862. Epub 2022 Nov 15.

Characterising heart rhythm abnormalities associated with Xp22.31 deletion

Georgina Wren #  1 , Emily Baker #  2   3 , Jack Underwood  3   4 , Trevor Humby  1   3   4 , Andrew Thompson  1   5 , George Kirov  3 , Valentina Escott-Price  3 , William Davies  6   3   4
Affiliations

Characterising heart rhythm abnormalities associated with Xp22.31 deletion

Georgina Wren et al. J Med Genet. 2023 Jul.

Abstract

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.

Keywords: Anemia; Arrhythmias, Cardiac; Dermatology; Gastrointestinal Diseases; Genetic Association Studies.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Responses to the vignette in adult men with XLI (n=21) (A) and adult female carriers (n=58) (B). AF, atrial fibrillation/flutter; XLI, X linked ichthyosis.
Figure 2
Figure 2
LocusZoom plots showing the SNPs most significantly associated with atrial fibrillation/flutter in the Xp22.31 deletion consensus interval in males (A) and females (B).
See this image and copyright information in PMC

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