Collagen & aortopathy gene abnormalities in Ehlers Danlos Syndrome (EDS) & sporadic Thoracic Aortic Aneurysm & Dissection (TAAD)

Introduction: Ehlers Danlos Syndrome(EDS) and Thoracic Aortic Aneurysm & Dissection (TAAD) comprise rare Mendelian vascular phenotypes associated with significant premature morbidity and mortality. New sequencing technologies may allow the better characterisation of their genetic basis, thereby informing clinical management and identifying novel molecular pathways. Methods: A combined strategy of targeted high-throughput sequencing to identify the mutational spectrum in known collagen and aortopathy-susceptibility genes and whole-exome sequencing to identify novel candidate genes was used in large cohorts of EDS (n=600+) and TAAD (n=1200+). Results: Using targeted sequencing in 177 EDS index cases, 32 pathogenic or likely pathogenic (P/LP) variants (including 9 new diagnoses) and 21 Variants of uncertain significance (VUS's) were identified. In 1,050 TAAD index cases, 61(5.8%) P/LP variants (30 in FBN1) and 209(20%) VUS's were identified. Only 47% of P/LP variant in FBN1 had a prior clinical diagnosis of Marfan syndrome and only 51% of P/LP variants in any gene (40% in FBN1) had a positive family history. Patients with any P/LP variant had a greater likelihood of: aortic dissection (OR 2.36), younger age < 50 years (OR 5.3) and positive family history (OR 3.4). Exome sequencing in 189 unrelated EDS index cases without a genetic diagnosis, revealed a novel disease-causing gene, C1R, in Periodontal EDS. Provisional candidate genes were prioritised in patients with classical EDS features without COL5A1/2 mutations. Exome sequencing with linkage analysis in a dominant TAAD pedigree revealed a potentially pathogenic deep intronic variant in FBN1 and 3 provisional candidate genes in a recessive Kyphoscoliosis EDS pedigree. Conclusion: This work has shown that targeted sequencing with new, high-throughput sequencing technology can be useful in revealing new genotype-phenotype relationships and directing genotype-specific clinical management in EDS and TAAD. Whole exome sequencing in well selected cases was also found to be useful in identifying novel genes underlying these phenotypes, thereby revealing a new pathogenic mechanism underlying connective tissue disease.