Gene Expression Study of Individuals with Sex Chromosome Aneuploidies

Males and females show dramatic differences in their vulnerability to the same diseases. For example, compared to men, lupus is six times more prevalent, thyroid cancer is three times more prevalent, and unipolar depression is twice as prevalent in women. Diseases with a strong male bias include autism (5:1), dilated cardiomyopathy (3:1), and ankylosing spondylitis (5:1). Historically, such differences have been attributed solely to extrinsic factors such as circulating sex hormones or environmental influences. We hypothesized that intrinsic factors - genetic differences between XX and XY cells - have unappreciated biological consequences throughout the body and contribute to sex differences in disease incidence and severity. This hypothesis stems from our long-term effort to sequence the sex chromosomes of diverse mammalian species, which has identified a set of homologous genes on the X and Y chromosomes that are dosage-sensitive, expressed throughout the body, and encode regulators of chromatin modification, transcription, translation, and protein stability. These X- and Y-encoded genes differ in sequence and expression pattern, which likely manifests in genome-wide differences in gene regulation between XX and XY cells and influences all aspects of human biology, including sex differences in disease susceptibility. These hard-wired molecular sex differences have been largely overlooked and understudied, representing a significant gap in our knowledge of human biology.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Full Transcriptome Sequencing
  • RNA Sequencing
• Total number of consented subjects: 220
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• Gene
• Clinical Trials
  • NCT01661010

We did not exclude any individuals based on factors relating to age, ethnicity, gender, or other findings, as long as potential participants have sex chromosome variations and satisfy all inclusion/exclusion criteria. This condition occurs in both genders, and in all ethnicities. This study may include decisionally impaired adults. Decisionally impaired individuals may be enrolled if the legal guardian consent or assent is obtained, when appropriate. Pregnant or nursing women will be limited in their participation in some aspects of the study (e.g. ionizing radiation exposure).

Inclusion Criteria:

• Male and female patients identified as having sex chromosome aneuploidy
• In the event that a patient with sex chromosome aneuploidy 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.
• Willing family members of subjects enrolled may be enrolled as control subjects.

Exclusion Criteria:

• Anyone unwilling to provide informed consent or assent
• Patients with medical conditions that would place them at high risk of complications if managed at the NIH clinical center (e.g. dialysis dependency, unstable cardiac conditions, or severe depression/suicidality).
• Cases that are clearly not related to sex chromosome aneuploidy or our direct research interests. However, this is a rare occurrence, and we would attempt to make referrals to a more appropriate investigator.

Adults (18+ years of age) with sex chromosome aneuploidies or euploid controls were recruited through an IRB-approved study at the NIH Clinical Center (12-HG-0181). Individuals with previous karyotype showing non-mosaic sex chromosome aneuploidy, or a structural variant of the sex chromosomes were included in the study. From these individuals, blood samples and skin biopsies were collected at the NIH Clinical Center and shipped to the Page Laboratory at Whitehead Institute for derivation of cells and analysis. Additional blood samples from adults or children, with sex chromosome aneuploidies, were contributed by Dr. Angela Lin at Massachusetts General Hospital, Dr. Carole Samango-Sprouse, and Dr. Rebecca Harris at Boston Children's Hospital under the approved protocol. Additional derived LCLs were obtained from the Colorado Children's Hospital Biobank and Coriell Research Institute, and cultured in the Page laboratory for at least two passages prior to collection for RNA-sequencing (RNA-seq). Karyotyping of peripheral blood and fibroblast cell cultures was performed at the National Human Genome Research Institute Cytogenetics and Microscopy Core. To reduce the impact of sex chromosome mosaicism on our sex chromosome aneuploidy analysis, we only included individuals with <15% mosaicism for other karyotypes.

• Primary Phenotype: Aneuploidy
• Sex Chromosome Aberrations

• ZFX
• ZFY
• DDX3X
• DDX3Y

• Co-Principal Investigators
  • David C. Page. Whitehead Institute, Cambridge, MA, USA.
  • Maximilian Muenke. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
• Funding Sources
  • U01 HG007587. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Focus Foundation. Davidsonville, MD, USA.