CIDR-NIA Whole Exome Analysis of Ehlers-Danlos Syndrome

The Ehlers-Danlos syndromes (EDS) are a family of hereditary disorders of connective tissue characterized by joint hypermobility and skin involvement with soft, translucent, stretchy skin, and atrophic scarring. To date, over 12 different types of EDS are known, and the genes causing almost all of them have been found. However, the gene(s) underlying the most common of Ehlers-Danlos syndrome, known as the hypermobile type, remain elusive. The hypermobile type of Ehlers-Danlos syndrome is associated with multiple co-morbidities, including dysautonomia, chronic musculoskeletal pain, gastrointestinal dysmotility, mast cell activation and multiple neurologic complications. Affected persons often suffer from chronic fatigue and may be chronically disabled. While the precise frequency of the condition is not known, it may be as common as between 1/500 and 1/1000 persons. There is a significant overlap with the phenotype of fibromyalgia, and multiple persons diagnosed with fibromyalgia may well have the hypermobile type of Ehlers-Danlos syndrome. The phenotype of hypermobile EDS segregates as a single dominant trait with complete penetrance, variable expressivity, and a markedly evolving phenotype over time. Identification of the genetic cause of this hereditary disorder has the potential to inform rational therapy for this disabling condition. It is hoped that the insight into the pathogenesis of the hypermobile type of EDS will lead to a similar breakthrough in therapy for this disorder. Toward this end, whole exome sequencing (WES) of DNA from a total of 167 patients will be performed at the Center for Inherited Disease Research (CIDR) to identify genes underlying the hypermobile type of Ehlers-Danlos syndrome and those with EDS of an uncharacterized type.]]>
Patients with a diagnosis of Ehlers-Danlos syndrome made by the principle investigator of the study or by a referring geneticist were included. Patients with the vascular form of Ehlers-Danlos as confirmed by molecular testing and documented COL3A1 mutations were excluded. Whole exome sequencing was performed on 167 patients with the hypermobile (110 patients) or the uncharacterized type (57 patients).]]>
Between 2001 and 2013, over 500 patients with Ehlers-Danlos syndrome were enrolled in a longitudinal study of Hereditary Connective Tissue Disorders at the National Institute on Aging. Of these, 110 were diagnosed with the hypermobile type and 183 were diagnosed as having EDS, but a specific type could not be assigned. The diagnosis of each participant was established by the principle investigator of the study or by a referring geneticist. Between 2014 and 2015, the clinical data on these patients were assembled into a relational database to support further interrogation of the data and deeper investigation into these disorders. During that process, the clinical data for each of the patients were put through a diagnostic algorithm for each of the major types of Ehlers-Danlos syndrome to provide confirmatory evidence of the clinical diagnosis. Almost all of the patients with the vascular form of Ehlers-Danlos had confirmatory molecular testing and documented COL3A1 mutations. However, no molecular testing was performed on the DNA from those patients with the hypermobile type or those with unknown types, as the genes underlying these phenotypes have yet to be ascertained. Based on the clinical features of patients in these disease categories, it is extremely unlikely that the gene(s) underlying their hereditary connective tissue disorder is one of the genes known to cause the other types of Ehlers-Danlos syndrome. The clinical phenotypes of the rarer types are well described, as are the phenotypes of the classical and vascular types of EDS. While many of these sub-types share clinical features with the hypermobile type, there are sufficient distinguishing characteristics to separate the groups.]]>