Systematic evaluation of 120 history and 40 physical findings (see all of them in Table S1 of the Supplemental Materials for the later article [16] ) found in the first 915 EDS patients was performed on three groups of EDS patients: 741 seen in clinic, 277 seen in clinic with retrospective form completion (many with salient DNA findings seen before the 120-finding forms were adopted), and 243 evaluated by online/telemedicine interaction where patients filled out the forms [16] [23] . This heterogeneity was counteracted by selecting more consistent findings for EDS group comparisons, based on the fact that women aged 21 - 40 years had very similar clinical profiles [16] . Finding frequencies, standard deviations, and coefficients of variation for their 21 - 25, 26 - 30, 31 - 35, and 36 - 40 year sub-groups were calculated [16] , reasoning that intergroup variation would reflect inconsistent reporting in this homogenous population. Results are shown in columns A-C and W-Y to the left of each finding in Supplemental Table 1 , the most consistent 50 findings among the 120 listed in rows 6-37 of that Table. Grouping by mechanism places findings reflecting hypermobility-injury [13] (10 findings), skeletal bend-deformation [18] (10), or skin fragility [15] (5) in Column D while those reflecting POTS [27] (10), IBS-MCAS [27] [28] [29] (10), and neuromuscular [19] (5) processes are in Column Z. Below the consistent findings in each of these columns are 5 selected findings listed because of implications for management. Several findings have been used as criteria for the hypermobile [13] or classical [15] types of EDS by 2017 criteria as indicated by superscripts (see the criteria in columns AU-AV of S1 Table in the previously published Supplemental Materials [16] ). Anxiety was one of 11 history findings systematically assessed in the POTS category, dividing EDS patients into those reporting (826) or not reporting (435) this finding (see Table 1 and Results-anxiety was therefore eliminated to make 10 findings in the POTS category).

The 1979 EDS outpatients including 967 with DNA testing were entered into a password-protected MS Excel^© GW patient database approved by the North Texas IRB (centered at Medical City Hospital, Dallas) in 2014 (exempt protocol number 2014-054). Contributing to the data in this article and available in the previously published Supplementary Materials [16] are deidentified Excel tables that 1) include the 1261 EDS patients with systematic evaluations with sex and age range demographics, type of evaluation, source of referral, detailed history-physical findings, and positive/negative but not specific DNA results (the EDS1261GW1-23 database, Sheets 5-6); 2) S2 Table summarizing the number of DNA variants by gene; 3) S3 Table listing the 917 DNA variants in 568 EDS patients, 893 qualified with 1 - 4+ relevance to EDS. The latter table, its patient numbers scrambled to protect identity, includes commercial [39] and clinical-biochemical [16] qualifications, ClinVar [40] or MitoMap [41] registration, and parental origin when determined.

Note: The 1261 EDS patients with systematic evaluations are listed by characteristic (left) or DNA testing results (right). EDS hypermobile [13] or classical [15] type diagnoses were assigned by 2017 consensus criteria, 37 patients having more dysautonomia than delineating joint-skin findings. Less common referrals from allergists, gastroenterologists, etc. for ~4% of EDS patients are not listed; *significant difference in proportions or averages, p < 0.05 (see Methods); SD, standard deviation.

Frequencies of the more reliable clinical findings in different EDS patient groups were tallied from the EDS1261GW1-23 database using the search, find, and sort functions of MS Excel© and are listed in Appended Table Ex1. Average frequencies, standard deviations, and significant differences at the p < 0.05 level were determined using Excel functions and online resources [42] [43] , the latter comparing means by two-tailed t and proportions by N-1 chi-squared tests.

Discussed in Methods was the selection of the 50 history-physical findings most consistently reported by EDS patients (per the statistics in columns A-C and W-Y of Table 1 ) and their grouping by tissue laxity (column D) or neuro- autonomic (Column Z) mechanisms. In red print are findings shared by patients with long COVID19 with their average frequencies and ranges from the survey of 64 articles by Deer et al. [35] .

Scanning the comprehensive data in Table 1 shows 1) that ratios of standard deviation to frequency (coefficients of variation) are under 0.05 for 14 findings and under 0.10 for 35 with only 4 above 0.15 (columns C, Y of Table 1 ); 2) higher frequencies in females (columns H, AD of Table 1 ) than males (columns N, AJ) for most findings except for six of body build/skeletal deformation (e. g., height, flat feet or toeing-in), two of infancy-early childhood (colic-feeding difficulty, motor delay), and having a 30% lower weight percentile than that for height; 3) higher frequencies in all EDS patients with anxiety for 7 of 10 findings related to joint laxity-injury, 4 of 10 related skeletal deformation, 3 of 5 related to skin fragility, 10 of 10 related to POTS, 8 of 10 related to IBS/MCAS, and 5 of 5 related to neuromuscular mechanisms; and 4) that most ratios of finding frequencies in patients with/without anxiety (columns T, AP) are between 1 and 1.3, most differences deriving from finding frequencies in the predominant females over age 21.

The increase of anxiety with age is detailed in Supplement Figure 1 , low proportions with anxiety under age 10 for both sexes, female proportions at 66% to 79% for older female decadal groups with a fall-off to 57% for those over 51 years. The younger presentation of males (52% between ages 10 and 20 compared to 26% of females) likely reflects their increased athletic activity since their mentioned muscle support produces milder numbers of symptoms overall ( Table 1 ). Only

the 21 - 30 age group in Figure 1 has a significant majority (63%) with anxiety.

Excerpted in Figure 1 are 30 individual EDS findings shaded by mechanistic group and ranked by indices designed to reflect their utility for suspecting EDS in the patient with general anxiety (data column 1 for all EDS patients). A high finding frequency (P) was considered most useful, multiplied by anxiety/no anxiety ratios (R) and consistency (coefficients of variation C) such that the arbitrary index I = P × R × 1/C is similar to P (Indices for every finding are shown all EDS patients (columns U, AP), females (columns K, AG), and males (columns Q, AM) of Table 1 .

Seven POTS findings in all EDS patients (yellow colors) top the list in Figure 1 , five of them frequent in long COVID19 [31] [35] , several of them (altered sweating, sleep issues, tachycardia, salt fancy) along with other POTS (altered sweating and syncope) and dysautonomia (gum disease plus caries, dysphagia, and bladder issues) having the highest anxiety/no anxiety ratios (1.30 to 1.64 in columns T, AP of Table 1 ). These findings of autonomic imbalance and their following neuromuscular findings (chronic daily headaches and muscle aches in Figure 1 , also seen in long COVID19) are more predictive than traditional skin (e.g. easy bruising, elasticity around jaw) or joint (e.g. reverse prayer, subluxations) findings.

The high rankings of neuro-autonomic findings [19] [21] [25] - [28] shows why they must be recognized as part of EDS if other diseases [35] [36] and DNA findings [23] are to be correlated. Finding categories support this mandate, their average indices highest for POTS (70), skin (66), and joint-flexibility-injury (61), lowest for skeletal deformations (52- Figure 1 ). Indices for the majority female (red) and male (blue) findings parallel those for all patients with exceptions of male heat-cold sensitivity, neuromuscular, and IBS findings.

Adding clinical considerations [23] to consensus descriptors [38] of DNA results (see Methods) qualified DNA variants or their combinations in 566 of 967 EDS patients as significant and contributory to their symptoms [16] [23] . A key aspect of this clinical qualification was the relation of variant genes to tissue laxity or autonomic mechanisms by reference to prior disease associations, summarized for 317 EDS-relevant genes in previous publications (S2 Tables of Supplementary Materials [16] [23] ) as excerpted for recurring gene variants in Table 2 . Gene changes are categorized by impact on particular tissue elements in the middle of Table 2 , including the 51 influencing collagen type V that, with their long EDS association [15] , reinforce the relevance of these DNA results [16] [23] . The lower rows of Table 2 show genes impacting neuro-autonomic processes in EDS based on their prior disease associations, a mechanism less anticipated unless one recognizes the cycle of vessel laxity to adrenergic imbalance [25] [26] that

Note: ¹percentages are of 566 patients with DNA results in the first data column, the percentage of those primary variants in EDS patients with or without anxiety shown in the second and third data columns. Of the 967 EDS patients having DNA testing, 31 were tested for alleles found in relatives, 30 with gene panels, and 906 with whole exome sequencing, DNA variants relevant to EDS were found in 566 patients, 2 of them having unrelated secondary findings [38] . A clinical qualification protocol added points for synergism with EDS-dysautonomia mechanisms to single (61%) or multiple (39%) DNA variant results, converting consensus [38] descriptors of uncertain significance/likely pathogenic/pathogenic to medical diagnostic utility scores [23] of 1+ (1 result-0.18% of 566), 2+ (29% - 5.1%), 3+ (123% - 22%), or 4+ (413% - 77%). *significant p < 0.05; gene abbreviations defined at www.omim.org; MNGIE, a mitochondrial neurogastrointestinal encephalopathy with predominant IBS symptoms.

through sensory-autonomic (small fiber) neuropathy [20] reciprocally enhances tissue laxity [26] [32] .

Note that 170% or 30.9% (16% + 10% + 4.9%) of the 566 EDS patients with relevant DNA findings have gene changes impacting tissue laxity (upper group in Table 2 ) and that 161% or 28% (2.8% + 16% + 2.5% + 1.8% + 4.9%) have changes impacting neuro-autonomic mechanisms (lower group in Table 2 ). Neurosensory/mitochondrial [23] [44] (75 versus 34 or 89%) and autonomic-inflammatory (40 versus 12 of or 77%) gene changes are more associated with anxiety than those of tissue laxity (only those of bone-joint-skin collagen genes are significant at 54 of 88 or 61%), correlating with the clinical mechanisms of Figure 1 . Genes involved in autonomic-inflammatory processes include the POLG mitochondrial DNA polymerase gamma [45] and the profilaggrin FLG gene [46] .