An extra X chromosome among adult women in the Million Veteran Program: A more benign perspective of trisomy X

Shanlee M Davis; Craig C Teerlink; Julie A Lynch; Natalia Klamut; Bryan R Gorman; Meghana S Pagadala; Matthew S Panizzon; Victoria C Merritt; Giulio Genovese; Judith L Ross; Richard L Hauger

doi:10.1002/ajmg.c.32083

An extra X chromosome among adult women in the Million Veteran Program: A more benign perspective of trisomy X

Am J Med Genet C Semin Med Genet. 2024 Mar 5:e32083. doi: 10.1002/ajmg.c.32083. Online ahead of print.

Authors

Shanlee M Davis^{1

2}, Craig C Teerlink^{3

4}, Julie A Lynch^{3

4

5}, Natalia Klamut^{1

2}, Bryan R Gorman⁶, Meghana S Pagadala^{7

8}, Matthew S Panizzon⁹, Victoria C Merritt^{10

11

12}, Giulio Genovese^{13

14

15}, Judith L Ross^{16

17}, Richard L Hauger^{9

10

11

12}

Affiliations

¹ Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
² eXtraOrdinarY Kids Clinic, Children's Hospital Colorado, Aurora, Colorado, USA.
³ VA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Healthcare System, Salt Lake City, Utah, USA.
⁴ Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah, USA.
⁵ College of Nursing and Health Sciences, University of Massachusetts, Lowell, Massachusetts, USA.
⁶ VA Boston Healthcare System, Boston, Massachusetts, USA.
⁷ Medical Scientist Training Program, University of California San Diego, La Jolla, California, USA.
⁸ Biomedical Science Program, University of California San Diego, La Jolla, California, USA.
⁹ Center for Behavioral Genetics of Aging, School of Medicine, University of California San Diego, La Jolla, California, USA.
¹⁰ VA San Diego Healthcare System, San Diego, California, USA.
¹¹ Department of Psychiatry, University of California San Diego, La Jolla, California, USA.
¹² Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, California, USA.
¹³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, Massachusetts, USA.
¹⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁵ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ Nemours Children's Hospital DE, Wilmington, Delaware, USA.
¹⁷ Department of Pediatrics, School of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

PMID: 38441278
DOI: 10.1002/ajmg.c.32083

Abstract

Despite affecting in 1 in every 1000 females, remarkably little is known about trisomy X syndrome (47,XXX), especially among older adults who are undiagnosed. In this study, we aimed to determine the prevalence of 47,XXX among females enrolled in the Million Veterans Program (MVP; mean age 50.2 ± 13.6 years), and compare broad health outcomes between females with 47,XXX and 46,XX matched controls. We identified 61 females with an additional X chromosome, corresponding to a prevalence of 103 per 100,000 females; 27.9% had been clinically diagnosed. Females with 47,XXX had taller stature (+6.1 cm, p < 0.001), greater rate of outpatient encounters (p = 0.026), higher odds of kidney disease (odds ratio [OR] = 12.3; 95% confidence interval [CI] 2.9-51.8), glaucoma (OR = 5.1; 95% CI 1.5-13.9), and congestive heart failure (OR = 5.6; 95% CI 1.4-24.2), and were more likely to be unemployed (p = 0.008) with lower annual income (p = 0.021) when compared with 46,XX controls of the same age and genetic ancestry. However, there were no differences in the rates of other encounter types, Charlson Comorbidity Index, all other medical and psychological diagnoses, military service history or quality of life metrics. In conclusion, in this aging and predominately undiagnosed sample, 47,XXX conferred few differences when compared with matched controls, offering a more reassuring perspective to the trisomy X literature.

Keywords: Million Veteran Program; healthcare utilization; morbidity; sex chromosome aneuploidy; triple X syndrome.

Abstract

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