Data analyzed for this report were derived from the GALAXY and INSIGHTS projects (Kanakatti Shankar et al., 2024), which collect clinically verified and self-report data from individuals with SCAs evaluated at 13 TS or SCA multidisciplinary clinics across the United States. Enrollment criteria included a genetically confirmed SCA diagnosis, which is validated for each participant by study staff. These analyses were conducted on the cross-sectional baseline dataset from both databases. Data were analyzed on all individuals with 1.) values for basic demographics and 2.) complete responses to the Research Priorities survey.

Individuals with an SCA (referred to henceforth as self-advocates) or caregivers of individuals with SCA (referred to henceforth as caregivers) could respond to the survey. The survey was completed at home using the online REDCap platform (Kanakatti Shankar et al., 2024) or in clinic on an iPad after enrollment into the study, and respondents included here completed the survey between February 23, 2023 and July 2, 2024.

Both surveys were designed and modified by the Steering Committee (SC) for each registry to be inclusive of the range of health topics that are relevant to individuals with SCAs and caregivers. The SCs are comprised of clinical experts, researchers, individuals with SCAs, and caregivers of individuals with SCAs, and is designed to bring together a variety of expertise, experience, and opinions. SC members contributed additional relevant survey topics and edited the surveys for clarity and acceptability.

Priority for several health topics and research study types were measured with a slider scale ranging from 0 to 100, with 0 indicating the lowest priority and 100 the highest priority. Participants were instructed to, “indicate how [they] would like to see research on this area prioritized for the X&Y community. Think about what is important to [them] and what [they] want resources to go toward.” Participants were also instructed that, although they may feel everything is important, to use both sides of the scale so we can tell which topics were of higher priority than others (full instructions in Appendix 1). Topic areas were broken into four categories: medical/physical health (28 topics), emotional/behavioral health (11 topics), other (15 topics), and research study types (6 topics), with minor variations between the INSIGHTS (TS only) and GALAXY (all other SCA) surveys (Appendix 1).

Descriptive statistics are stratified by SCA condition and presented for demographics as N (%) for categorical variables and median [IQR] for continuous variables. SCA subgroups are defined as: Turner syndrome (45,X and variants), Trisomy X (47,XXX), Klinefelter syndrome (47,XXY and mosaic), 47,XYY syndrome, 48,XXYY syndrome, and SCA-other (combined rare tetrasomies and pentasomies). Demographic differences between SCA groups were tested using Kruskal-Wallis tests for continuous variables, and Fisher’s Exact tests for categorical variables. Age reflects the age of the individual with an SCA at the date of survey response. Research priorities for each SCA condition are visualized as boxplots, depicting median [IQR]. Within each research domain (physical health, types of studies, emotional/behavioral health, and other health), research priorities are shown for the top 10 topics, given the median is greater than 50. Within domains that contained fewer than 10 research topics, all topics with a median greater than 50 are plotted. Self-advocate versus caregiver, as well as INSIGHTS versus GALAXY and prenatal versus postnatal diagnostic timing, scores are summarized as median [IQR] with differences tested using Wilcoxon Rank Sum tests. All analyses are interpreted under the assumption of a type 1 error rate of 0.05 for unadjusted p-values as well as False Discovery Rate (FDR) adjusted p-values to rule out truly null results. A supplemental analysis of scores stratified by private vs non-private insurance was conducted using Wilcoxon Rank Sum tests. Comparison of research priorities are visualized using heatmaps, with the heatmap.2 R function within the gplots package, version 3.1.3.1, with columns and rows sorted by hierarchical clustering using Euclidean distance. All analyses were performed in R, version 4.4.0.

A total of 303 of 629 (48.1%) participants (251 caregivers and 52 self-advocates) completed the survey (Table 1). The sample was stratified by SCA diagnosis, with the largest cohort diagnosed with TS (n=144), followed by KS (n=86), XXYY syndrome (n=35), and Trisomy X (n=17). Self-advocate participants were a median of 35.1 years old with a range from 13.4 to 73.8 years. The children of caregiver respondents were a median of 7.7 years old with a range from 3 weeks to 35.7 years. There was evidence that respondent type varied by SCA subgroups, where only caregivers of individuals with XYY, XXYY, and SCA-other responded and no self-advocates. More than three-fourths (79.9%) of respondents identified as White Non-Hispanic, and there was not sufficient evidence to conclude differences in racial or ethnic identity between SCA subgroups. Additionally, most participants (59.5%) held private insurance, with a higher proportion of participants with private insurance in the KS and TS groups (68.6 and 61.1% respectively) as compared to other SCA groups. Respondents represented ten multidisciplinary clinics across the United States, with the greatest (40.8%) from Children’s Hospital Colorado (CHCO); there was evidence that site of enrollment was different between SCA groups because only the CHCO and Online sites enrolled individuals with supernumerary SCAs.

The top priorities overall in the TS participant group (Figure 1, Supplemental Table 1) were anxiety disorders (82 [67, 97.5]), fertility concerns (82 [68.5, 99]), and social deficits (80 [65, 96]). The top priorities in the Trisomy X group (Figure 2) were learning disabilities (96 [71, 100]), medical and healthcare access (89 [66.5, 100]), and, similar to the TS group, anxiety disorders (88 [75, 100]). The top priorities overall in the KS group (Figure 3) were similar to the TS group as well: hormone replacement therapy (94.5 [75, 100]), fertility concerns (88.5 [69.25, 100]), and learning disabilities (82 [67, 98]) tied with strengths-based research (82 [69.75, 98]). The top priorities overall in the XYY group, all caregiver respondents (Figure 4), were fertility concerns (100 [59.5, 100]), learning disabilities (98.5 [72.5, 100]), and self-harm/suicidality (93.5 [71.5, 100]). The top priorities in the XXYY group, all caregiver respondents again (Figure 5), were social deficits (91 [73, 98.5]), quality of life (87 [77.5, 98]), and hormone replacement therapy (85 [75, 97.5]) tied with self-sufficiency (85 [76, 98). The SCA-other group included all but one caregiver respondents. The top priorities overall in this group (Figure 6) were social deficits (85 [65, 92]), understanding X and Y variations (80 [70, 85]), and learning disabilities (78 [72, 95]) tied with self-sufficiency (78 [67, 97]).

Interventional studies were identified as the highest research priority among all groups (82 [69, 97]). Additionally, all study types had a median score above 50 for all SCA groups.

The median scores and differences for self-advocates and caregivers across all physical, emotional-behavioral, other health topics, and research study types are presented in Table 2. We did not adjust for insurance status as there was no evidence that insurance status differed between caregiver and self-advocate respondents.

Caregivers rated developmental delays as a significantly higher research priority, with a median score of 78.5 [58.75–97], substantially greater than the median of 58 [18–77] from self-advocates (p<0.001). This pattern of statistical significance was also observed for seizures where caregivers had a median score of 50 (IQR : [26.5–75]), compared to a median score of 19.5 [3–29.5] reported by self-advocates (p<0.001).

Furthermore, caregivers viewed self-sufficiency as a significantly more important research priority, with a median score of 80 [61–97], than self-advocates, who scored it at a median of 68 [31–82] (p=0.003). Similarly, caregivers rated fertility-related concerns higher, with a median of 81.5 [51.5–100], compared to a median of 33 [8–83] reported by self-advocates (p=0.004). Self-advocates rated medical/healthcare access as a higher research priority (85 [80–99]) than caregivers (76 [50–94], p=0.012).

After False Discovery Rate (FDR) adjustments, there were no significant correlations between age and any of the priority topics in the self-advocate group. Dental/orthodontic problems were significantly associated with insurance status (private: 58 [39, 76]; non-private: 75 [62, 88], p=0.023) after FDR adjustment (Supplemental Table 3). Several topics showed a higher priority in privately vs. non-privately insured participants prior to FDR adjustment, including dental problems, cardiovascular problems, seizures, sleep problems, tremor, and autism, whereas the opposite as true for fertility and HRT priority ratings.

In comparing timing of diagnosis to research priorities, a sub-analysis included 135 individuals diagnosed with their SCA prenatally and 101 who were diagnosed postnatally. Fertility concerns (prenatal 91 [72, 100]; postnatal 76 [50, 94.5], p-value 0.008) and hormone replacement therapy (prenatal 91.5 [71, 100]; postnatal 79 [63, 96], p-value 0.047) were significantly higher in prenatally than postnatally diagnosed respondents after FDR adjustment. Additionally, before FDR adjustment, developmental delays (prenatal 79 [58.5, 95]; postnatal 71 [50, 86], p-value 0.019) and prenatal counseling/pregnancy (prenatal 86 [67.8, 100]; postnatal 71.5 [55.8, 85.5], p-value 0.003) showed similar results. However, sleep problems (prenatal 50 [29, 69]; postnatal 63.5 [32.8, 77], p-value 0.018), lymphedema (prenatal 36 [16, 65]; postnatal 59 [31.2, 77.2], p-value 0.019), self-sufficiency (prenatal 76 [50, 93]; postnatal 79.5 [64.2, 97], p-value 0.037), and social deficits (prenatal 74 [57, 87]; postnatal 80 [68, 96], p-value 0.041) had the opposite result such that they were significantly higher in postnatally than prenatally diagnosed respondents.

Additionally, within the postnatally diagnosed subgroup, some correlations between research priorities and age at diagnosis were found, such that a higher age at diagnosis led to a lower priority for cardiovascular problems (−0.25, p-value <0.001), developmental delays (−0.28, p-value <0.001), self-sufficiency (−0.30, p-value <0.001), hearing loss (−0.28, p-value 0.001), allergies, asthma, or eczema (−0.36, p-value 0.001), recurrent infections (−0.33, p-value 0.004), transition to adult healthcare (−0.21, p-value 0.019), seizures (−0.20, p-value 0.027), and liver problems (−0.18, p-value 0.046). After FDR adjustment, only three remained significant: cardiovascular problems (−0.25, p-value <0.001), developmental delays (−0.28, p-value 0.003), and self-sufficiency (−0.30, p-value 0.008).

Based on hierarchical clustering analysis (Figure 7), the research priorities of TS participants are most similar to those of the ‘all other SCA’ group, while the Trisomy X and XXYY groups show the greatest similarity to each other. XYY respondents tended to rate research priorities higher than other groups. Across all groups, anxiety disorders, ADD/ADHD, depression or mood problems, learning disabilities, social deficits, and interventional studies are rated similarly high.

Not all groups had a sufficient sample size to compare self-advocate responses to caregiver responses. Those that could be compared are visualized in Figure 8. Based on the hierarchical analysis, caregivers of Trisomy X and XYY patients were clustered together, with their joint highest rated category being learning disabilities. Caregivers of KS and XXYY were clustered together and similarly rated hormone replacement therapy high but differed in their ratings of fertility concerns, where caregivers of KS rated this higher, possibly due to the more severe presentation of other health concerns in XXYY. Self-advocates and caregivers of TS were clustered together while self-advocates and caregivers of KS were not. Both self-advocates and caregivers of KS rated hormone replacement therapy high, however, self-advocates rated fertility concerns much lower.

Survey responses were compared between participants in the INSIGHTS and GALAXY registries and are reported in Supplemental Table 2. After FDR adjustment for multiple comparisons, participants in the GALAXY registry rated dental/orthodontic problems significantly higher than participants in the INSIGHTS registry (65.5 [42.25, 83] and 50 [24.5, 71] respectively, p = 0.004). Participants in the INSIGHTS registry rated hearing loss (p < 0.001), cardiovascular problems (p < 0.001), vision or eye problems (p = 0.008), skin problems (p = 0.041), eating disorders (p = 0.003), transition from pediatric to adult care (p = 0.010), and observational studies (p < 0.001) significantly higher than participants in the GALAXY registry.

The findings of this analysis should be used to help guide future research in subjects with SCAs. The numerous overlapping priorities among SCA subgroups may enable researchers to conduct transdiagnostic group studies with increased sample size and statistical power. At the same time, we also identified unique features that distinguish the SCA subgroups, and careful considerations should be made to avoid over-generalizing among the diagnoses. Results highlight the importance of a multidisciplinary focus for addressing research needs of the SCA population. To be responsive to SCA community priorities, SCA researchers are encouraged to collaborate and target research efforts toward clinical trial readiness and interventional studies for both medical and psychological manifestations of SCA conditions.