Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome

Abstract

Background: Ehlers-Danlos syndrome (EDS) is a common non-inflammatory, congenital connective tissue disorder. Classical type (cEDS) EDS is one of the more common forms, typically caused by mutations in the COL5A1 and COL5A2 genes, though causative mutations in the COL1A1 gene have also been described. Material and methods: The study group included 59 patients of Polish origin, diagnosed with cEDS. The analysis was performed on genomic DNA (gDNA) with NGS technology, using an Illumina sequencer. Thirty-five genes related to connective tissue were investigated. The pathogenicity of the detected variants was assessed by VarSome. Results: The NGS of 35 genes revealed variants within the COL5A1, COL5A2, COL1A1, and COL1A2 genes for 30 of the 59 patients investigated. Our panel detected no sequence variations for the remaining 29 patients. Discussion: Next-generation sequencing, with an appropriate multigene panel, showed great potential to assist in the diagnosis of EDS and other connective tissue disorders. Our data also show that not all causative genes giving rise to cEDS have been elucidated yet.

Clinical-Genomic Analysis of 1261 Patients with Ehlers–Danlos Syndrome Outlines an Articulo-Autonomic Gene Network (Entome)

“…Findings relating to all three of these processes must be included in the diagnostic guidelines for EDS and be holistically evaluated when deciding if a clinical profile warrants separation as a distinctive EDS type. Genomic analyses [ 10 , 11 , 12 , 13 , 14 ] must also acknowledge these articulo-autonomic mechanisms if its potential for EDS precision medicine is to be realized.…”

“…Advantaging this genomic approach requires equally broad perspectives on diseases like Ehlers–Danlos syndrome (EDS, [ 4 ]), evaluating all of its joint (articular) and neurovascular (autonomic) [ 5 ] findings rather than the few highlighted by rare types [ 6 , 7 , 8 ]. If EDS is recognized in its most common form, affecting a significant portion of the 10 to 20 percent satisfying “double-jointed” criteria [ 1 , 9 ], then more studies will be added to those [ 10 , 11 , 12 , 13 , 14 ] finding multiple gene alterations in EDS patients.…”

A gene network implicated in the joint-muscle pain, brain fog, chronic fatigue, and bowel irregularity of Ehlers-Danlos and “long” COVID19 syndromes

“…1 qualification of DNA results as relevant to EDS findings are the similar numbers of history-physical findings (35-18) among EDS patients having DNA variants (DNA+ in Table 1) as those without (DNA-, 35-19). The most likely explanation for this is incomplete discovery of EDS-contributing genes, prior exome studies finding 9 variant genes in 177 patients [1], 4 in 59 patients [3] and even the present 330 variant genes in 568 patients (317 relevant to EDS) not including mutations outside of exons or exon-intron borders. Support for EDS-DNA correlation by the Fig 1 protocol will follow its discussion and include differences from disability patient results (S4 Table) and the recurring gene variants of S2, S3 Tables.…”

“…Study of the human being, limited by causal foibles of chance and necessity, can nevertheless take advantage of a large organism privileged by centuries of detailed observation. Human systems biology can begin with the Review of Systems required for medical evaluation, a holistic approach nicely complemented by NextGen detailing of genome sequence change [1][2][3]. While the contingencies of disease pattern will never match the controlled insights from experimental study, holistic documentation of symptoms and their translation into pathogenetic mechanisms can focus molecular investigation.…”

“…Although initial analyses of connective tissue disorders focused on tethering proteins like collagens [1][2][3][4][5][6][7], its necessary role in protist to metazoan transitions [14] requires that connecting tissue be medium [15][16][17][18][19][20][21] and message [12,[22][23][24][25][26][27][28]. The result in complex organisms that combine internal homeostasis with external movement is a diversity of constraining and connecting structures [skin, joint, skeleton-15-21] permeated by wired [nerve [12][13][22][23][24][25], moving [muscle [26][27][28] and circulating [heart-vessel 7] parts.…”