The Clinical Study of Sex Chromosome Variants

The Clinical Study of Patients With Sex Chromosome Variants

Purpose/Lay Summary: Background:

- Chromosomes are the structures inside of each cell that carry our genetic material (genes). Certain differences in the sex chromosomes are known to cause various diseases, such as infertility, Turner syndrome, or Klinefelter syndrome. However, it is not fully understood why these differences are seen and what clinical findings may be caused with different sex chromosome variants. This study is seeking to learn more about the genetic and clinical characteristics of disorders related to the X and Y chromosomes.

Objectives:

- To study related medical conditions in people with sex chromosome variants.

Eligibility:

• Patients with known sex chromosome differences may be eligible to participate.
• Healthy volunteers age 18 - 55

Design:

• Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
• This study will last about 5 days. Participants will have a variety of endocrine and other tests. They will provide blood, urine, and semen samples for these tests.
• Imaging studies of the heart and abdomen will be performed. These tests may include ultrasounds and magnetic resonance imaging.
• Participants will also have their vision and hearing checked.
• Healthy volunteers with have a single day visit for a medical history, physical exam, and blood and skin samples.
• Treatment will not be provided as part of this study.
• Compensation is offered.

Study Overview

• Status: Completed
• Conditions: Male Factor Infertility; Female Factor Infertility

Detailed Description

Infertility is a disease that affects approximately 10% of couples world-wide. Causes of infertility are varied and include age-related decline in fecundity, other causes of ovulatory dysfunction, tubal and pelvic pathology, male causes, idiopathic, and multifactorial. The underlying genetic causes of infertility are incompletely understood. The purpose of this study is to increase our understanding of the genetic and clinical manifestations of infertility related to sex-chromosome variants through detailed physical, radiologic, and laboratory studies. We will concentrate on a group of patients (both male and female) with known sex-chromosome variationsfully characterized through genetic sequencing and karyotyping. Other patients with

sex chromosome variants will be invited depending on the variant described. Patients recruited and consenting to this study will be evaluated at the NIH Clinical Center

• Study Type: Observational
• Enrollment (Actual): 112

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients previously identified through outside research or diagnostic labs as having sex-chromosome variants causing deletion/duplication of sex-linked genes or entire sex chromosomes.@@@

Description

• INCLUSION CRITERIA:

  1. Patients previously identified through outside research or diagnostic labs as having sex-chromosome variants causing deletion/duplication of sex-linked genes or entire sex chromosomes, male and female.
  2. In the event that a patient with a sex-chromosome variant self-refers to the protocol, medical records will be reviewed by a committee to include Dr. David Page, Dr. Maximilian Muenke, and others to decide whether the patient is appropriate for enrollment in the protocol.
  3. Willing family members of subjects enrolled may be enrolled as control subjects.

EXCLUSION CRITERIA:

1. We reserve the right to exclude patients with medical conditions that would place a potential participant at high risk of complications if managed at the NIH clinical center (ex. dialysis dependency, unstable cardiac conditions, unstable severe depression/suicidality).
2. We reserve the right to exclude cases that are clearly not related to sex-chromosome variants, infertility or our direct research interests (e.g. infertility with clearly non-genetic etiology). This almost never happens, and we would attempt to make referrals to a more

appropriate investigator.

It is our intention to try to remove as many economic, cultural, geographic, racial, and gender barriers as we reasonably can to promote a diverse participation of sex-chromosome variant cases for research purposes.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Control; Family members can serve as control group
Sex-linked genes; Patients previously identified through outside research or diagnostic labs as having sex-chromosome variants causing deletion/duplication of sex-linked genes or entire sex chromosomes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phenotype	To characterize the physical, reproductive, endocrinologic and radiologic phenotype of a group of patients who have known sex-chromosome structural and copy-number variants.	Ongoing
Spectrum	To examine the spectrum of clinical characteristics of infertility and other conditions related to sex-chromosome variants and facilitate early clinical recognition, diagnostic confirmation, anticipatory management, prognostication, and proper genetic counseling.	Ongoing

Collaborators and Investigators

• Sponsor: National Human Genome Research Institute (NHGRI)
• Investigators: Principal Investigator: Ashley J Buscetta, C.R.N.P., National Human Genome Research Institute (NHGRI)

Publications and helpful links

General Publications

• Brandell RA, Mielnik A, Liotta D, Ye Z, Veeck LL, Palermo GD, Schlegel PN. AZFb deletions predict the absence of spermatozoa with testicular sperm extraction: preliminary report of a prognostic genetic test. Hum Reprod. 1998 Oct;13(1O):2812-5. doi: 10.1093/humrep/13.10.2812.
• Bondy CA; Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007 Jan;92(1):10-25. doi: 10.1210/jc.2006-1374. Epub 2006 Oct 17.
• Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990 Nov 29;348(6300):448-50. doi: 10.1038/348448A0.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2012

Study Registration Dates

• First Submitted: August 7, 2012
• First Submitted That Met QC Criteria: August 7, 2012
• First Posted (Estimated): August 9, 2012

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: January 9, 2024

More Information

Terms related to this study

• Keywords: Infertility; Natural History; Turner Syndrome; Aneuploidy; X-Chromosome; Y-Chromosome
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Infertility
• Other Study ID Numbers: 120181; 12-HG-0181

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No