Repository logo

Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome.

Published version

Repository DOI

Change log


Vandersteen, Anthony M 
Weerakkody, Ruwan A  ORCID logo
Parry, David A 
Kanonidou, Christina 
Toddie-Moore, Daniel J 


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.


Peer reviewed: True

Acknowledgements: The study was supported by the National Institute for Health Research England (NIHR) for the NIHR BioResource project (grant number RG65966). We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource Centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We acknowledge Julie Leary and Cherida Watkins (NWLH) for their assistance with recruitment and administrative support. This study also makes use of data generated by the UK10K Consortium, derived from samples from ALSPAC; a full list of the investigators who contributed to the generation of this data is available from Funding for the UK10K was provided by the Wellcome Trust under award WT091310.


Genetic Testing, Human Genetics, Musculoskeletal Diseases, Rheumatology, Child, Humans, Genome-Wide Association Study, Longitudinal Studies, Ehlers-Danlos Syndrome, Connective Tissue Diseases

Journal Title

J Med Genet

Conference Name

Journal ISSN


Volume Title


Wellcome Trust (UK10K, WCMA_P43883, WT091310)
NIHR (RG65966)