Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome.

Genetic Testing Human Genetics Musculoskeletal Diseases Rheumatology

Journal

Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R

Informations de publication

Date de publication:
09 Oct 2023
Historique:
received: 10 04 2023
accepted: 18 09 2023
medline: 15 10 2023
pubmed: 15 10 2023
entrez: 9 10 2023
Statut: aheadofprint

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND 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 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 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 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.

Identifiants

DOI: 10.1136/jmg-2023-109329 PMID: 37813462
pubmed: 37813462
pii: jmg-2023-109329
doi: 10.1136/jmg-2023-109329
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: TA is co-founder and director of the company BioCaptiva. There are no other competing interests.

Auteurs

Anthony M Vandersteen (AM)

Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada tim.aitman@ed.ac.uk anthony.vandersteen@dal.ca.
Faculty of Medicine, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Ruwan A Weerakkody (RA)

Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Institute of Clinical Sciences, Imperial College London, London, UK.
Department of Vascular Surgery, Royal Free Hospital, London, UK.
ORCID: 0000-0002-6717-7383

David A Parry (DA)

Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Christina Kanonidou (C)

Department of Clinical Biochemistry, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK.

Daniel J Toddie-Moore (DJ)

Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Jana Vandrovcova (J)

Department of Neuromuscular Diseases, UCL Queen Street Institute of Neurology, University College London, London, UK.

Rebecca Darlay (R)

Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.

Javier Santoyo-Lopez (J)

Edinburgh Genomics, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0003-1988-5059

Alison Meynert (A)

MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK.

Hanadi Kazkaz (H)

Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK.

Rodney Grahame (R)

Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK.

Carole Cummings (C)

Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, UK.

Marion Bartlett (M)

Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, UK.

Neeti Ghali (N)

Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, UK.
ORCID: 0000-0003-2847-1376

Angela F Brady (AF)

Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, UK.

F Michael Pope (FM)

Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, UK.

Fleur S van Dijk (FS)

Ehlers-Danlos Syndrome National Diagnostic Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Department of Metabolism, Digestion and Reproduction Section of Genetics and Genomics, Imperial College London, London, UK.

Heather J Cordell (HJ)

Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.

Timothy J Aitman (TJ)

Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK tim.aitman@ed.ac.uk anthony.vandersteen@dal.ca.
ORCID: 0000-0002-7875-4502

Classifications MeSH