RT Journal Article
SR Electronic
T1 Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 232
OP 238
DO 10.1136/jmg-2023-109329
VO 61
IS 3
A1 Vandersteen, Anthony M
A1 Weerakkody, Ruwan A
A1 Parry, David A
A1 Kanonidou, Christina
A1 Toddie-Moore, Daniel J
A1 Vandrovcova, Jana
A1 Darlay, Rebecca
A1 Santoyo-Lopez, Javier
A1 Meynert, Alison
A1 ,
A1 Kazkaz, Hanadi
A1 Grahame, Rodney
A1 Cummings, Carole
A1 Bartlett, Marion
A1 Ghali, Neeti
A1 Brady, Angela F
A1 Pope, F Michael
A1 van Dijk, Fleur S
A1 Cordell, Heather J
A1 Aitman, Timothy J
YR 2024
UL http://jmg.bmj.com/content/61/3/232.abstract
AB 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.Data are available on reasonable request.