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. 2026 Jan;200(1):23-34.
doi: 10.1002/ajmg.a.64214. Epub 2025 Aug 13.

Generating Advancements in Longitudinal Analysis in X and Y Variations: Rationale, Methods, and Diagnostic Characteristics for the GALAXY Registry

Alexandra Carl  1   2 , Samantha Bothwell  2 , Karli Swenson  2 , Ryan Bregante  1   3 , Lilian Cohen  1   4 , Virginia Cover  1   5 , Anna Dawczyk  1   6 , Gail Decker  1   7 , Stephen B Gerken  1 , David Hong  1   8 , Susan Howell  1   2   9 , Armin Raznahan  1   10 , Alan D Rogol  1   11 , Nicole Tartaglia  1   2   9 , Shanlee Davis  1   2   12
Affiliations

Generating Advancements in Longitudinal Analysis in X and Y Variations: Rationale, Methods, and Diagnostic Characteristics for the GALAXY Registry

Alexandra Carl et al. Am J Med Genet A. 2026 Jan.

Abstract

Sex chromosome aneuploidies (SCAs) are a family of genetic disorders that result from an atypical number of X and/or Y chromosomes. SCAs are the most common chromosomal abnormality, affecting ~1/400 live births, yet are often underdiagnosed, leading to over-representation of more severely impacted individuals in many clinical studies. In addition to this ascertainment bias, existing work in SCAs has also been limited by low geographic and demographic diversity. To address these limitations, we have created the Generating Advancements with Longitudinal Analysis in X and Y variations (GALAXY) Registry. Through prioritizing sustainability, transparency, and minimizing participant burden, the overarching goal of the GALAXY Registry is to improve health outcomes for individuals with SCAs by serving as an infrastructure for future SCA research based on a large, heterogeneous, and longitudinal sample. To date, GALAXY has accrued 335 verified SCA participants with an average accrual of 11.2 participants/month (6.7 47,XXY, 1.9 47,XXX, 2.0 47,XYY, 3.2 48,XXYY, 1.8 48,XXXY, and 1.3 Other). Demographic data between those identified to have SCA prenatally (predominantly cell-free DNA screening) differ from those diagnosed postnatally for insurance status, age at enrollment, genetic test type, and reason for SCA diagnosis. Next steps include targeted recruitment of underrepresented groups (e.g., non-47,XXY karyotypes, older adults, minoritized individuals), extraction of medical record data into the registry, international expansion, and continued engagement with the SCA community. As a collaboration between clinician investigators and the SCA community, the GALAXY Registry is a powerful resource for future patient-centered clinical research.

Keywords: Klinefelter syndrome; XXY; XXYY; XYY; registry; sex chromosome aneuploidies; trisomy X.

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