Editing Ehlers–Danlos syndrome (section)

===Hypermobile ===
Hypermobile EDS (hEDS, formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. It may lead to frequent joint [[subluxations]] (partial dislocations) and dislocations. In general, people with this variant have skin that is soft, smooth, and velvety and bruises easily, and may have chronic muscle or bone pain.<ref name="GARD2017"/> It affects the skin less than other forms. It has no available genetic test.<ref name="Levy_2018"/> hEDS is the most common of the 19 types of connective tissue disorders. Since no genetic test exists, providers have to diagnose hEDS based on what they know about the condition and the patient's physical attributes. Other than the general signs, attributes can include faulty connective tissues throughout the body, musculoskeletal issues, and family history. Along with these general signs and side effects, patients can have trouble healing.<ref>{{cite web|url=https://www.ehlers-danlos.org/what-is-eds/information-on-eds/hypermobile-eds-and-hypermobility-spectrum-disorders/|title=Hypermobile EDS and Hypermobility Spectrum Disorders| vauthors = Carter K | work = Ehlers–Danlos Support UK}}</ref>

Pregnant individuals who have hEDS are at an increased risk for complications. Some possible complications are pre-labor rupture of membranes, a drop in blood pressure with anesthesia, [[precipitate delivery|precipitated birth]] (very fast, active labor), malposition of the fetus, and increased bleeding. Individuals with hEDS may run the risk of falling, [[postpartum depression]] (more than the general population), and slow healing from the birthing process.<ref>{{cite web|url=https://www.ehlers-danlos.org/information/pregnancy-birth-feeding-and-hypermobile-ehlers-danlos-syndrome-hypermobility-spectrum-disorders/|title=Pregnancy, birth, feeding, and hypermobile Ehlers–Danlos syndrome/hypermobility spectrum disorders | work = The Ehlers–Danlos Support UK|access-date=2019-11-22}}</ref>

The Medical University of South Carolina discovered a gene variant common with hEDS patients.<ref>{{Cite web | vauthors = Cantu L | date = 14 July 2021 |title=MUSC researchers announce gene mutation discovery associated with EDS |url=https://web.musc.edu/about/news-center/2021/07/14/musc-researchers-announce-gene-mutation-discovery-associated-with-eds-ehlers-danlos |access-date=2023-02-08 | work = Medical University of South Carolina}}</ref>

====Genetics====

While 12 of the 13 subtypes of EDS have genetic variations that can be tested for by [[genetic testing]], there is no known genetic cause of hEDS. Recently, several labs and research initiatives have been attempting to uncover a potential hEDS gene. In 2018, the [[Ehlers–Danlos Society]] began the Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study.<ref>{{cite web |url=https://www.ehlers-danlos.com/hedge/|title=HEDGE Study| website= ehlers-danlos.com| publisher= | date= | access-date=}}</ref> The ongoing study has screened over 1,000 people who have been diagnosed with hEDS by the 2017 criteria to evaluate their genome for a common mutation. To date,{{When|date=March 2025}} 200 people with hEDS have had [[whole genome sequencing]], and 500 have had whole [[Exome sequencing|exome]] sequencing; this study aims to increase those numbers significantly. <ref>{{cite web |url=https://www.ehlers-danlos.com/hedge/|title=HEDGE Study| website= ehlers-danlos.com| publisher= | date= | access-date=}}</ref>

Promising outcomes of this increased screening have been reported by the Norris Lab, led by Russell Norris, in the Department of Regenerative Medicine and Cell Biology at [[Medical University of South Carolina]].<ref>{{cite web |url=https://www.thenorrislab.com/home|title= About the Lab| publisher= Norris Lab, [[Medical University of South Carolina]]| date= | access-date=}}</ref> Using [[CRISPR]] Cas-9 mediated genome editing on mouse models of the disease, the lab has recently identified a "very strong candidate gene"<ref>{{cite journal | vauthors = Gensemer C, Burks R, Kautz S, Judge DP, Lavallee M, Norris RA | title = Hypermobile Ehlers–Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes | journal = Developmental Dynamics | volume = 250 | issue = 3 | pages = 318–344 | date = March 2021 | pmid = 32629534 | pmc = 7785693 | doi = 10.1002/dvdy.220}}</ref> for hEDS. This finding, and a greater understanding of cardiac complications associated with the majority of EDS subtypes, has led to the development of multiple druggable pathways involved in [[Aorta|aortic]] and [[mitral valve]] diseases. While this candidate gene has not been publicly identified, the Norris lab has conducted several studies involving small population genome sequencing and come up with a working list of possible hEDS genes. A mutation in [[Collagen, type III, alpha 1|''COL3A1'']]<ref>{{cite journal | vauthors = Narcisi P, Richards AJ, Ferguson SD, Pope FM | title = A family with Ehlers–Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen | journal = Human Molecular Genetics | volume = 3 | issue = 9 | pages = 1617–1620 | date = September 1994 | pmid = 7833919 | doi = 10.1093/hmg/3.9.1617}}</ref> in a single family with autosomal dominant hEDS phenotype was found to cause reduced collagen secretion and an over-modification of collagen. In 35 families, copy number alterations in ''[[TPSAB1]]'',<ref>{{cite journal | vauthors = Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, Ho N, Zhao M, Liu Y, O'Connell MP, Trivedi NN, Nelson C, DiMaggio T, Jones N, Matthews H, Lewis KL, Oler AJ, Carlson RJ, Arkwright PD, Hong C, Agama S, Wilson TM, Tucker S, Zhang Y, McElwee JJ, Pao M, Glover SC, Rothenberg ME, Hohman RJ, Stone KD, Caughey GH, Heller T, Metcalfe DD, Biesecker LG, Schwartz LB, Milner JD | title = Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number | journal = Nature Genetics | volume = 48 | issue = 12 | pages = 1564–1569 | date = December 2016 | pmid = 27749843 | pmc = 5397297 | doi = 10.1038/ng.3696}}</ref> encoding alpha-tryptase, were associated with increased basal serum [[tryptase]] levels, associated with [[Dysautonomia|autonomic dysfunction]], [[Gastrointestinal disease|gastrointestinal disorders]], allergic and cutaneous symptoms, and connective tissue abnormalities, all concurrent with hEDS phenotype. An unknown number of people diagnosed with hEDS may have a reduced [[Tenascin X]],and/or mutations in the [[TNXB]] gene.<ref>Zweers, Manon C et al. “Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome.” American journal of human genetics vol. 73,1 (2003): 214-7. doi:10.1086/376564</ref><ref name="Kaufman_2016">{{cite journal | vauthors = Kaufman CS, Butler MG | title = Mutation in TNXB gene causes moderate to severe Ehlers-Danlos syndrome | journal = World Journal of Medical Genetics | volume = 6 | issue = 2 | pages = 17–21 | date = May 2016 | pmid = 28344932 | pmc = 5363719 | doi = 10.5496/wjmg.v6.i2.17 | doi-access = free }}</ref>

Another way the Norris lab is attempting to find this gene is by looking at genes involved in the formation of the aorta and mitral valves, as these valves are often prolapsed or malformed as a symptom of EDS. Because hEDS is such a complex, multi-organ disease, focusing on one hallmark trait has proven successful. One gene found this way is ''[[DZIP1]]'', which regulates cardiac valve development in mammals through a [[CBY1]]-beta-catenin mechanism. Mutations at this gene affect the [[Catenin beta-1|beta-catenin]] cascade involved in development, causing malformation of the extracellular matrix, resulting in loss of collagen. A lack of collagen here is consistent with hEDS and explains the "floppy" mitral and aortic valve heart defects. A second genetic study specific to mitral valve prolapse focused on the [[Platelet-derived growth factor|PDGF]] signaling pathway, which is involved in growth factor ligands and receptor isoforms.<ref>{{cite journal | vauthors = Moore K, Fulmer D, Guo L, Koren N, Glover J, Moore R, Gensemer C, Beck T, Morningstar J, Stairley R, Norris RA | title = PDGFRα: Expression and Function during Mitral Valve Morphogenesis | journal = Journal of Cardiovascular Development and Disease | volume = 8 | issue = 3 | date = March 2021 | page = 28 | pmid = 33805717 | doi = 10.3390/jcdd8030028 | pmc = 7999759 | doi-access = free}}</ref> Mutations in this pathway affect the ability to localize [[cilia]] in various cell types, including cardiac cells. With the resulting [[ciliopathies]], structures such as the [[cardiac outflow tract]], [[heart tube]] assembly, and cardiac fusion are limited and/or damaged.{{citation needed|date=September 2022}}