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X-chromosome Inactivation, Epigenetics and the Transcriptome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01678261
Recruitment Status : Completed
First Posted : September 3, 2012
Last Update Posted : May 24, 2016
Lundbeck Foundation
The Korning Foundation Denmark
AP Moeller Foundation
Information provided by (Responsible Party):
University of Aarhus

Brief Summary:

The human genetic material consists of 46 chromosomes of which two are sex chromosomes. The sex-chromosome from the mother is the X and from the father the Y-chromosome. Hence a male consist of one Y and one X chromosome and a female of 2 X-chromosomes. Alterations in the number of sex-chromosomes and in particular the X-chromosome is fundamental to the development of numerous syndromes such as Turner syndrome (45,X), Klinefelter syndrome (47,XXY), triple X syndrome (47,XXX) and double Y syndrome (47,XYY). Despite the obvious association between the X-chromosome and disease only one gene has been shown to be of significance, namely the short stature homeobox gene (SHOX). Turner syndrome is the most well characterized and the typical diseases affecting the syndrome are:

  • An Increased risk of diseases where one's own immune system reacts against one's own body (autoimmune diseases) and where the cause of this is not known; For example diabetes and hypothyroidism.
  • Increased risk of abortion and death in uteri
  • Underdeveloped ovaries with the inability to produce sex hormones and being infertile.
  • Congenital malformations of the major arteries and the heart of unknown origin.
  • Alterations in the development of the brain, especially with respect to the social and cognitive dimensions.
  • Increased incidence obesity, hypertension, diabetes and osteoporosis.

In healthy women with to normal X-chromosomes, the one of the X-chromosomes is switched off (silenced). The X-chromosome which is silenced varies from cell to cell. The silencing is controlled by a part of the X-chromosome designated XIC (X-inactivation center). The inactivation/silencing of the X-chromosome is initiated by a gene named Xist-gene (the X inactivation specific transcript).This gene encodes specific structures so called lincRNAs (long intervening specific transcripts) which are very similar to our genetic material (DNA) but which is not coding for proteins. The final result is that women are X-chromosome mosaics with one X-chromosome from the mother and the other X from the father. However, numerous genes on the X-chromosome escape this silencing process by an unknown mechanism. Approximately two third of the genes are silenced, 15 % avoid silencing and 20 percent are silenced or escape depending on the tissue of origin.

The aforementioned long non-protein-coding parts of our genetic material (LincRNAs) are abundant and produced in large quantities but their wole as respect to health and disease need further clarification. Studies indicate that these LincRNAs interact with the protein coding part of our genetic material modifying which genes are translated into proteins and which are not. During this re-modelling there is left foot prints on the genetic material which can indicate if it is a modification that results in silencing or translation of the gene. It is possible to map these foot prints along the entire X-chromosome using molecular techniques like ChIP (Chromatin immunoprecipitation) and ChIP-seq (deep sequencing).

The understanding achieved so far as to the interplay between our genetic material and disease has arisen from genetic syndromes which as the X-chromosome syndromes are relatively frequent and show clear manifestations of disease giving the researcher a possibility to identify genetic material linked to the disease. Turner and Klinefelter syndrome are, as the remaining sex chromosome syndromes, excellent human disease models and can as such help to elaborate on processes contributing to the development of diseases like diabetes, hypothyroidism, main artery dilation and ischemic heart disease.

The purpose of the study is to:

  1. Define the changes in the non-coding part of the X-chromosome.
  2. Identify the transcriptome (non-coding part of the X-chromosome)as respect to the RNA generated from the X-chromosome.
  3. Identify changes in the coding and non-coding parts of the X-chromosome which are specific in relation to Turner syndrome and which can explain the diseases seen in Turner syndrome.
  4. Study tissue affected by disease in order to look for changes in the X-chromosome with respect to both the coding and non-coding part of the chromosome.

6. Determine if certain genes escape X-chromosome silencing and to establish if this is associated with the parent of origin.

Condition or disease
Turner Syndrome Klinefelter Syndrome Triple X Syndrome 47 XYY Syndrome Aortic Aneurysm

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Study Type : Observational
Actual Enrollment : 110 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: X-chromosome Inactivation, Epigenetics and the Transcriptome
Study Start Date : September 2012
Actual Primary Completion Date : October 2015
Actual Study Completion Date : January 2016

1a Turner syndrome 45,X
Blood from 50 persons with Turner syndrome an karyotype 45,X
1b Controls for TS 45,X
50 healthy aged female controls matched to the TS 45,X cohort
2a Turner syndrome 45,X mosaics
Blood from 50 persons with Turner syndrome an karyotype 45,X mosaics
2b Controls for TS 45,X mosaics
50 healthy aged female controls matched to the TS 45,X mosaics cohort
3a Paraffin embedded aortic tissue TS
3a Paraffin embedded samples of aortic tissue from 10 persons with TS
3b Paraffin embedded aortic tissue from 10 controls
3b Paraffin embedded samples of aortic tissue from 10 controls who did not die from aortic aneurism
4a 70 47,XXY men
4a Blood from 70 men with Klinefelter syndrome (47,XXY)
4b 70 controls matching group 4a
4b 70 male controls matching group 4a with respect to age.
5a 5 persons with double Y-syndrome
5a Blood from 5 persons with double Y-syndrome (47,XYY)
5b 20 controls matching 5a
5b 20 healthy controls matching group 5a with respect to age
6a 5 persons with triple X-syndrome
6a Blood from 5 persons with triple X-syndrome (47,XXX)
6b 20 controls matching 6a
6b 20 healthy controls matching group 6a with respect to age.
7 10 biological parents of cohort 1a.
7 Blood from 10 biological parents of individuals in cohort 1a

Primary Outcome Measures :
  1. DNA-methylation of CpG-islands. [ Time Frame: Once ]
    mapping DNA-methylations of CpG-islands

  2. Histone modifications [ Time Frame: Once ]
    Permissive and repressive histone modifications on the X-chromosome

  3. mRNA and nonRNA [ Time Frame: Once ]
    identification of the entire transcriptome including both mRNA and non-coding RNAs (lincRNA as well as miRNA)from the X-chromosome

Biospecimen Retention:   Samples With DNA

Whole blood


White cells


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Individuals with sex chromosome syndromes will be recruited from out-patient clinics Controls will be recruited from the general population

Controls should fore fill the criteria below

Inclusion Criteria:

  • Healthy
  • Age matched

Exclusion Criteria:

  • Any chronic or acute illness thought to influence the outcome measures

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01678261

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Department of Endocrinology and Internal medicine
Aarhus, Denmark, 8000
Sponsors and Collaborators
University of Aarhus
Lundbeck Foundation
The Korning Foundation Denmark
AP Moeller Foundation
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Study Director: Claus H Gravholt, MD Aarhus University Hospital
Principal Investigator: Christian Trolle, MD Aarhus University Hospital
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: University of Aarhus Identifier: NCT01678261    
Other Study ID Numbers: 19668
First Posted: September 3, 2012    Key Record Dates
Last Update Posted: May 24, 2016
Last Verified: June 2015
Keywords provided by University of Aarhus:
Sex chromosome
Turner Syndrome
Klinefelter Syndrome
Triple X Syndrome
47 XYY syndrome
Aortic Aneurysm
non-coding RNA
Additional relevant MeSH terms:
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Turner Syndrome
Gonadal Dysgenesis
Klinefelter Syndrome
Aortic Aneurysm
XYY Karyotype
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Aortic Diseases
Disorders of Sex Development
Urogenital Abnormalities
Sex Chromosome Disorders of Sex Development
Heart Defects, Congenital
Cardiovascular Abnormalities
Heart Diseases
Congenital Abnormalities
Sex Chromosome Disorders
Chromosome Disorders
Genetic Diseases, Inborn
Gonadal Disorders
Endocrine System Diseases
Abnormal Karyotype
Chromosome Aberrations
Sex Chromosome Aberrations