Research Priorities of Individuals and Families with Sex Chromosome Aneuploidies

Abstract

Sex chromosome aneuploidies (SCAs) are chromosomal variations that result from an atypical number of X and/or Y chromosomes. Combined, SCAs affect ~1/400 live births, including individuals with Klinefelter syndrome (47,XXY), Turner syndrome (45,X and variants), Double Y syndrome (47,XYY), Trisomy X (47,XXX), and rarer tetrasomies and pentasomies. Individuals with SCAs experience a wide variety of physical health, mental health, and healthcare experiences that differ from the standard population. To understand the priorities of the SCA community we surveyed participants in two large SCA registries, the Inspiring New Science in Guiding Healthcare in Turner Syndrome (INSIGHTS) Registry and the Generating Advancements in Longitudinal Analysis in X and Y Variations (GALAXY) Registry. 303/629 (48.1% response rate) individuals from 13 sites across the United States responded to the survey, including 251 caregivers and 52 self-advocates, with a range of ages from 3 weeks to 73 years old and represented SCAs including Turner syndrome, XXX, XXY, XYY, XXYY, and combined rare tetrasomies and pentasomies. Results demonstrate the priorities for physical health and emotional/behavioral health identified by the SCA community, as well as preferred types of research. All SCA subtypes indicated intervention studies as the top priority, emphasizing the need for researchers to focus on clinical treatments in response to priorities of the SCA community.

Keywords: Klinefelter syndrome; Sex chromosome aneuploidies; Trisomy X; Turner syndrome; XXY; XXYY; XYY; research priorities.

Figure 1.. Turner syndrome research priorities

Research priorities among the Turner syndrome sample (n=144), including physical health, emotional/behavioral health, and other health domains, and types of research studies. Topics with a median greater than 50 are presented, capped at the top 10 topics per domain. The top physical health priorities reported by this group were fertility concerns (median [IQR] : 82 [68.5, 99]), hormone replacement therapy (81, [68, 97]), and cardiovascular problems 79 [65, 99]. The top emotional/behavioral health priorities were anxiety disorders (82 [67, 97.5]), social deficits (80 [65, 96]), and learning disabilities (79 [64.5, 96]). The top other health priorities were quality of life (82 [64, 99]), transition from pediatric to adult care (79 [67.5, 97]), and prenatal diagnosis/counseling (75.5 [60.5, 95]).

Figure 2.. Trisomy X research priorities

Research priorities among the Triple X sample (n=17), including physical health, emotional/behavioral health, types of studies, and other health domains. Topics with a median greater than 50 are presented, capped at the top 10 topics per domain. The top physical health priorities reported were fatigue and low energy (82 [69, 96]), fertility concerns (73.5 [38.75, 94.75]), and gastrointestinal problems (69.5 [56.75, 80.5]). The top emotional/behavioral health priorities were learning disabilities (96 [71, 100]), anxiety disorders (88 [75, 100]), and social deficits (87 [68, 98]). The top other health priorities were medical or healthcare access (89 [66.5, 100]), educating families and patients (88 [73.75, 100]), and understanding X and Y variations (84 [72.25, 97]).

Figure 3.. Klinefelter syndrome research priorities

Research priorities among the Klinefelter syndrome sample (n=86), including physical health, emotional/behavioral health, types of studies, and other health domains. Topics with a median greater than 50 are presented, capped at the top 10 topics per domain. The top physical health priorities reported were hormone replacement therapy (94.5 [75, 100]), fertility concerns (88.5 [69.25, 100]), and fatigue and low energy (78.5 [63.75, 99]). The top emotional/behavioral health priorities were learning disabilities (82 [67, 98]), depression or mood problems (77 [63.5, 90]), and anxiety disorders (77 [64, 86]). The top other health priorities were strengths-based research (82 [69.75, 98]), medical or healthcare access (81 [63.75, 96]), and understanding X and Y variations (80 [67.75, 98]).

Figure 4.. XYY research priorities

Research priorities among the XYY sample (n=12), including physical health, emotional/behavioral health, types of studies, and other health domains. Topics with a median greater than 50 are presented, capped at the top 10 topics per domain. The physical health priorities were fertility concerns (100 [59.5, 100]), growth differences (92 [65.5, 100]), and cancers (75 [43.5, 96]). The top emotional/behavioral health priorities were learning disabilities (98.5 [72.5, 100]), self-harm and suicidality (93.5 [71.5, 100]), and social deficits (88 [73.25, 100]). The top other health priorities were strengths-based research (90.5 [89.25, 98]), self-sufficiency (87 [73.5, 96.25]), and quality of life (82 [74, 98]).

Figure 5.. XXYY syndrome research priorities

Research priorities among the XXYY sample (n=35), including physical health, emotional/behavioral health, types of studies, and other health domains. Topics with a median greater than 50 are presented, capped at the top 10 topics per domain. The top physical health priorities reported were hormone replacement therapy (85 [75, 97.5]), fatigue or low energy (79.5 [69.75, 91.5]), and dental/orthodontic concerns (78.5 [67.25, 88]). The top emotional/behavioral health priorities were social deficits (91 [73, 98.5]), developmental delays (82 [68, 98]), and depression or mood problems (81 [54.5, 91.5]). The top other health priorities were quality of life (87 [77.5, 98]), self-sufficiency (85 [76, 98), and understanding X and Y variations (81 [73, 87]).

Figure 6.. All other SCAs research priorities

Research priorities among the sample of all other SCAs (n=9), including tetrasomies and pentasomies, including physical health, emotional/behavioral health, types of studies, and other health domains. Topics with a median greater than 50 are presented, capped at the top 10 topics per domain. The top physical health priorities were bone health (74 [59, 81]), autoimmune disorders (69 [62, 73]), and hormone replacement therapy (68 [68, 79]). The top emotional/behavioral health priorities were social deficits (85 [65, 92]), learning disabilities (78 [72, 95]), and autism (74 [50, 93]). The top other health priorities were understanding X and Y variations (80 [70, 85]), self-sufficiency (78 [67, 97]), and strengths-based research (76 [63, 84.25]).

Figure 7.. Research Priorities Heatmap of Median Ratings by SCA Diagnosis

Heatmap of median rating of research priorities by SCA, with both rows and columns sorted by hierarchical clustering to distinguish patterns between groups and priorities. Lighter colors represent lower rated priorities, with a minimum median of 25 and a maximum median of 100. Column lines represent the order of clustering, with paired lines (Trisomy X and XXYY as well as All Other SCAs and Turner Syndrome) represent SCAs that are most similar according to the clustering algorithm.

Figure 8.. Research Priorities Heatmap of Median Ratings by SCA Diagnosis and Survey Respondent

Heatmap of median rating of research priorities by SCA and survey respondent, with both rows and columns sorted by hierarchical clustering to distinguish patterns between groups and priorities. Lighter colors represent lower rated priorities, with a minimum median of 3 and a maximum median of 100. Only groups with > 5 respondents are included in the figure. Column lines represent the order of clustering, with paired lines (such as Trisomy X and XYY Caregivers) represent groups that are most similar according to the clustering algorithm.