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Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome

Lookup NU author(s): Dr Rebecca Darlay, Professor Heather Cordell

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. Background: The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown. Methods: Whole exome sequencing (WES) was undertaken on 174 EDS patients recruited from a national diagnostic service for complex EDS and a specialist clinic for hEDS. Patients had already undergone expert phenotyping, laboratory investigation and gene sequencing, but were without a genetic diagnosis. Filtered WES data were reviewed for genes underlying Mendelian disorders and loci reported in EDS linkage, transcriptome and genome-wide association studies (GWAS). A genetic burden analysis (Minor Allele Frequency (MAF) <0.05) incorporating 248 Avon Longitudinal Study of Parents and Children (ALSPAC) controls sequenced as part of the UK10K study was undertaken using TASER methodology. Results: Heterozygous pathogenic (P) or likely pathogenic (LP) variants were identified in known EDS and Loeys-Dietz (LDS) genes. Multiple variants of uncertain significance where segregation and functional analysis may enable reclassification were found in genes associated with EDS, LDS, heritable thoracic aortic disease (HTAD), Mendelian disorders with EDS symptomatology and syndromes with EDS-like features. Genetic burden analysis revealed a number of novel loci, although none reached the threshold for genome-wide significance. Variants with biological plausibility were found in genes and pathways not currently associated with EDS or HTAD. Conclusions: We demonstrate the clinical utility of large panel-based sequencing and WES for patients with complex EDS in distinguishing rare EDS subtypes, LDS and related syndromes. Although many of the P and LP variants reported in this cohort would be identified with current panel testing, they were not at the time of this study, highlighting the use of extended panels and WES as a clinical tool for complex EDS. Our results are consistent with the complex genetic architecture of EDS and suggest a number of novel hEDS and HTAD candidate genes and pathways.


Publication metadata

Author(s): Vandersteen AM, Weerakkody RA, Parry DA, Kanonidou C, Toddie-Moore DJ, Vandrovcova J, Darlay R, Santoyo-Lopez J, Meynert A, Kazkaz H, Grahame R, Cummings C, Bartlett M, Ghali N, Brady AF, Pope FM, Van Dijk FS, Cordell HJ, Aitman TJ

Publication type: Article

Publication status: Published

Journal: Journal of Medical Genetics

Year: 2024

Volume: 61

Issue: 3

Pages: 232-238

Print publication date: 21/02/2024

Online publication date: 09/10/2023

Acceptance date: 18/09/2023

Date deposited: 09/11/2023

ISSN (print): 0022-2593

ISSN (electronic): 1468-6244

Publisher: BMJ Publishing Group

URL: https://doi.org/10.1136/jmg-2023-109329

DOI: 10.1136/jmg-2023-109329

Data Access Statement: Data are available on reasonable request.

PubMed id: 37813462


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Funding

Funder referenceFunder name
NIHR
RG65966
UK10K WT091310
Wellcome Trust
WCMA_P43883

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