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Hypermobile Ehlers-Danlos Syndrome (hEDS) is a condition with heterogeneous clinical features characteristic of a connective tissue disorder (CTD) including generalized joint hypermobility, hyperextensible skin, joint subluxations/dislocations and commonly associated comorbidities such as postural orthostatic tachycardia syndrome and fatigue (Castori et al., 2017; Gensemer et al., 2021). hEDS is the only one among 13 Ehlers-Danlos syndrome (EDS) subtypes without a known etiology or targeted clinical molecular genetic testing, requiring strict clinical diagnostic guidelines and exclusion of other similar conditions (Malfait et al., 2017). Possibly due to the diverse clinical symptoms and the lack of molecular confirmation, hEDS referrals for evaluation for hEDS may be increasingly inundating and overwhelming genetics clinics. This study was a retrospective chart review that analyzed 143 referrals for suspected hEDS/CTD to the University of California, Irvine (UCI) adult genetics clinic and the referring providers’ relevant medical notes, if available. The purpose of this research was to understand why medical professionals refer patients with suspected hEDS/CTD for genetic evaluation and what they document in the referral. First, a classification scheme to identify appropriate referrals was developed using a consensus process. Utilizing a system with four categories of appropriateness, 51% (N=74) of referrals were found to lack enough details to be categorized as appropriate. Additionally, features recorded in the referral documentation were analyzed, and many features related to CTD aside from joint involvements either had not been assessed or were not documented. Many referrals (>75%) also did not document the presence or absence of certain CTD-related features including dislocations, subluxations, easy bruising, and elastic skin. Furthermore, the classification of appropriateness for the primary care referrals differed significantly from that for the referrals

Ehlers-Danlos Syndrome (EDS) describes a group of 14 heritable connective tissue disorders that have in common joint hypermobility. The most prevalent of the subtypes is the recently reclassified hypermobile EDS (hEDS) characterized by generalized joint hypermobility, skin features such as velvety texture and/or skin hyperextensibility, and musculoskeletal pain. Secondary features include autonomic dysfunction, gastrointestinal dysfunction, and fatigue. While the most prevalent EDS subtype, hEDS is the least understood without any consensus on associated causal genes or variants. Due to its complex and heterogeneous symptomatology, we hypothesize that hEDS is a genetically heterogenous disorder but with primary causal variants and/or genes. The focus of this dissertation, as part of the hEDS GENE study led by Dr. Christina Laukaitis, is to define the updated hEDS phenotype and identify both structural and rare single nucleotide variants that contribute to the hEDS phenotype. To explore the 2017 hEDS reclassification, 148 people were enrolled in the hEDS GENE study with 98 meeting the 2017 hEDS criteria, 27 having a hypermobility spectrum disorder (HSD) and 23 being asymptomatic family members. More than 80% of the participants were female. Each participant completed seven clinal questionnaires to thoroughly describe and quantify hEDS symptomatology including the 36-Item Short Form Health Survey, a subscale of the full Patient Health Questionnaire, the Tampa Scale for Kinesiophobia, the Fatigue Severity Scale, the Epworth Sleepiness Scale, the Gastro-Questionnaire, and a short form version of the Composite Autonomic Symptom Score. We concluded that symptom frequency and severity were generally indistinguishable between participants with hEDS and HSDs with both experiencing significant decrease in health-related quality of life, however, we also observed subtle differences in autonomic symptoms between the two hypermobile groups. In participants with a clearly-defined