Heritable disorders of connective tissue: Description of a data repository and initial cohort characterization

Abstract

We describe a data repository on the heritable disorders of connective tissue (HDCT) assembled by the National Institutes of Health’s National Institute on Aging (NIA) Intramural Research Program between 2001 and 2013. Participants included affected persons with a wide range of heritable connective tissue phenotypes, with clinical diagnoses updated in 2015, and unaffected family members. Elements include a comprehensive history and physical examination, standardized laboratory data, physiologic measures and imaging, standardized patient-reported outcome measures centered on overall health, pain, sleep and fatigue and an extensive linked biorepository. The NIA made a commitment to make the repository available to extramural investigators and deposited samples at the Coriell Tissue Repository (N=126) and GenTAC registry (N=132). The clinical dataset (“HDCT NIA Dataset v.2016”) was transferred to Penn State University College of Medicine Clinical and Translational Science Institute in 2016, and data elements and structure inventoried. The consented cohort of 1009 participants averaged 39 ± 18 years (mean ±SD, range 2-95) at consent; gender distribution is 71% F and 29% M, and 83% self-report Caucasian ethnicity. Diagnostic categories include Ehlers-Danlos Syndrome (Classical N=50, Hypermobile N=99, Vascular N=101, Rare Types and Unclassified N=178), Marfan Syndrome (N=33), Stickler Syndrome (N=60), Fibromuscular Dysplasia (N=135), Other HDCT (N=72). Unaffected family members (N=218) contributed DNA for the molecular archive only. We aim to develop further discrete data from unstructured elements, analyze multi-symptom HDCT manifestations, encourage data use by other researchers and thereby better understand the complexity of these high-morbidity conditions and their multifaceted effects on affected persons.

Arterial Elasticity in Ehlers-Danlos Syndromes

“…In 2016, a signed Data Transfer Agreement between NIA and Penn State University resulted in transfer of a copy of the HDCT NIA Dataset v.2016 data repository to the Penn State University Clinical Translational Science Institute (PSU-CTSI). Datasets were accompanied by copies of original CRFs and SAS dataset codebook descriptions [14].…”

“…Participants were stratified by EDS type including: classical, hypermobile, vascular, or other or unclassified according to the Villefranche nosology [15] as previously described for this cohort [14]. Briefly, classical EDS was determined by joint laxity and skin that is extremely hyperextensible, fragile, bruises easily, and has thin atrophic scars.…”

“…Finally, we acknowledge the heterogeneity of our EDS participants as a potential problem. Since these data were collected prior to the 2017 reclassification of EDS [1,14,15]. It is possible that some participants classified as having hypermobile or unspecified EDS would be categorized as hypermobility spectrum disorders using current criteria.…”

Features of heritable disorders of connective tissue in children with acute rheumatic fever and rheumatic heart disease

“…More than 200 heritable disorders of connective tissue (HDCT) have been described so far [1]. These disorders are caused by mutations of the genes responsible for building connective tissues and affecting collagen, elastin, muco-polysaccharides, or enzymes regulating their metabolism [2,3]. Disorders in connective tissue development leads to changes in homeostasis at all levels of metabolism and, subsequently, to morphological and functional disorders of different organs and systems.…”

“…There are different types of HDCT. The most recognized are: Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, Stickler syndrome, and fibromuscular dysplasia [3]. Underlying genetic mutations have been identified for many disorders of the connective tissue [4,5].…”