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Lookup NU author(s): Dr Rebecca Darlay, Professor Heather Cordell
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.
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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