Sex Chromosome AbnormalityEMKISCANCT05425953
Endocrine, Metabolic, Cardiovascular and Immunological Aspects of Sex Chromosome Abnormalities in Relation to Genotype
An observational study of Sex Chromosome Abnormality and Klinefelter Syndrome, run by University of Aarhus at 1 site in Denmark.
Trial summary
Observational study of 160 patients with sex-chromosome abnormalities and 160 matched controls. Blood, fat, muscle, skin, buccal swaps, urine will be collected and analyzed for DNA, RNA and methylation patterns. Read more about this study
- Who is it for?
- Ages 18 to 90 yearsHealthy volunteers can take part
- Conditions the study is for
- Sex Chromosome Abnormality, Klinefelter Syndrome, Turner Syndrome
- How many people
- 320 participants
- Where
- 1 siteDenmark
- Study dates
- 13 Jun 2022to 1 May 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Study population are danish participants.
Who may be able to join
- Participants must have the sex-chromosome abnormality
Who cannot join
- -
Trial locations and contacts
1 site in 1 country.
Denmark1 site, 1 recruiting
- Recruiting
Aarhus university hospital
Aarhus, Region Midt, 8000
Lukas O Ridder, MD, 25337447 ext. 0045, Lukrid@clin.au.dk
Claus Gravholt, Prof., claus.gravholt@clin.au.dk
About this study
Official title: Endocrine, Metabolic, Cardiovascular and Immunological Aspects of Sex Chromosome
Observational study of 160 patients with sex-chromosome abnormalities and 160 matched controls. Blood, fat, muscle, skin, buccal swaps, urine will be collected and analyzed for DNA, RNA and methylation patterns. The goal is to associated genotype and epigenetic changes with the phenotype of patients with sex-chromosome abnormalities.
Patients participate in questionaries, dexa-scan of bones, fibroscan of liver, ultra sound of testicles and blood will be analyzed for organ specific blood work as well as immunological and coagulation components.
Read the detailed description
Background: The most prevalent SCAs are Klinefelter syndrome (KS; 47, XXY), 47,XXX, 47,XYY and Turner syndrome (TS; 45,X) with a prevalence of 85-250, 84, 98 and 50 per 100,000 liveborn boys/girls, respectively. The majority of SCAs can suffer from a range of diseases including congenital malformations, metabolic diseases, hypergonadotropic hypogonadism and infertility, autoimmune disease and psychiatric diseases. However, the genetic mechanisms causing these phenotypes are largely unexplained. The phenotypes have been suggested to arise from alterations in DNA methylation and RNA-expression. The methylome and transcriptome in peripheral blood samples from persons with KS, 47,XXX and TS have been found to be altered in comparison with controls. These genes are now starting to be found ex. SHOX, located in the pseudo autosomal region of the X and Y chromosome, escapes X-inactivation and is therefore equivalent to the number of sex chromosomes. Altered expression of SHOX in SCAs has been associated with the altered height seen in these patients.
Hypotheses:
- The methylome and transcriptome of SCAs is altered compared to karyotypical normal female and males, and a unique methylation profile and RNA expression profile is seen for the different SCAs subgroups.
- The methylation profile and the RNA expression profile show temporal alterations.
- The DNA methylation profile and the RNA expression profile are tissue-specific.
- The phenotype and the increased risk of diseases seen in patients with SCAs are associated with the altered RNA-expression and DNA methylation profile.
Materials: Blood, fat, muscle, skin, buccal swaps, urine, will be collected from 60 klinefelter, 60 Turner syndrome patient, 20: 47, XXX and 20: 47, XYY and 80 male and female matched controls.
Methods:
Analysis of DNA-methylation using Whole Genome Bisulfite Sequencing (WGBS). Genomic DNA will be bisulfite-converted and sequenced on an Illumina Novaseq System. Sequence data pre-processors of software pipeline MethylStar. Analyzed using R.
Gene expression analysis (RNA) RNA will be cleaned and sequenced with a sequence depth of 30 million reads. Processing of sequence data using FastQC (quality control), HISAT2 (mapping) and featureCounts (gene-expression). Differences in gene-expression will be analyzed in R.
The extracted biopsies will be dissociated to singular cells RNA from these singular cells will be individually sequenced. For miRNA analysis we will isolate small non-coding RNAs and analyze these by next generation sequencing. Chromatin re-modelling can be analyzed through "footprints" left by histones on DNA-strand. Mapping of footprints along the whole X-chromosome is done using a single assay with chromatin-immunoprecipitation (CHIP) in combination med deep sequencing (chIPseq).
Genotype-Phenotype association analysis with weighted correlation network analysis (WGCNA) we will uncover the patterns in which genes behave and divide them into modules where genes react dependent of each other. These modules will afterwards be associated with the clinical data, enabling identification of the "hub" genes with the strongest associations to the phenotype.
These gene-modules, and the gene expression data itself, can furthermore be included in "deep-phenotyping" using artificial intelligence Perspectives A characterization of the methylome and transcriptome from different target tissue from patients with SCAs would not just be of significance to these patients but could lead to a larger understanding of similar diseases in patients without SCAs. Using SCAs as disease models and identify changes in DNA methylation and RNA-expression related to co-morbidity such as the metabolic syndrome, congenital heart disease or psychiatric diseases could increase the understanding of these diseases in general and potentially improve treatment in other patients groups with similar diseases.
In addition, the data collection will expand our biobank and will enable future research projects about SCAs.
- Conditions
- Sex Chromosome Abnormality, Klinefelter Syndrome, Turner Syndrome, Metabolic Disease, Cardiovascular Diseases, Immunologic Disease
- Being tested
- No intervention other than obtaining biopsies
- Medical subject headings
- Sex Chromosome Aberrations, Klinefelter Syndrome, Turner Syndrome, Metabolic Diseases, Cardiovascular Diseases, Immune System Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
No intervention other than obtaining biopsiesOther
Biopsies will be obtained.
| Study group | Role | What they receive |
|---|---|---|
| Klinefelter syndrome | Patients with 47, XXY n=60 Receives: Other: No intervention other than obtaining biopsies | |
| Turner syndrom | Patients with 45, X n=60 Receives: Other: No intervention other than obtaining biopsies | |
| 47, XXX | Patients with 47, XXX n=20 Receives: Other: No intervention other than obtaining biopsies | |
| 47, XYY | Patients with 47, XYY n=20 Receives: Other: No intervention other than obtaining biopsies | |
| Male controls | Male controls n=80 Receives: Other: No intervention other than obtaining biopsies | |
| Female controls | Female controls n=80 Receives: Other: No intervention other than obtaining biopsies |
What is being measured
The primary outcome is the main question the study is designed to answer.
Epigenetic changes relate to phenotype
Epigenetic changes relate to phenotype
Measured: 2½ years
Secondary outcomes (1)
Immunologic changes in turner syndrom
Patients with Turner syndrome may have altered immunological properties
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jun 2022
- Study start13 Jun 2022
- Primary completion1 May 2025 (estimated)
- Study completion1 May 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Sex Chromosome AbnormalityStudies of the same condition, open and under way.
- More trials run by University of AarhusThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 320 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- Collaborators
- Aarhus University Hospital
- Responsible party
- Sponsor
- Investigators
- Claus Gravholt, Prof, Study director, Aarhus University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05425953
- Sponsor's protocol ID
- EMKI SCA
- Acronym
- EMKISCA
- Status last verified
- Nov 2023
- First submitted
- 15 Jun 2022
- Last updated
- 29 Nov 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Roulot D, Degott C, Chazouilleres O, Oberti F, Cales P, Carbonell N, Benferhat S, Bresson-Hadni S, Valla D. Vascular involvement of the liver in Turner's syndrome. Hepatology. 2004 Jan;39(1):239-47. doi: 10.1002/hep.20026.
PubMed 14752843Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebaek A. Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr Rev. 2018 Aug 1;39(4):389-423. doi: 10.1210/er.2017-00212.
PubMed 29438472de Vos WM, Tilg H, Van Hul M, Cani PD. Gut microbiome and health: mechanistic insights. Gut. 2022 May;71(5):1020-1032. doi: 10.1136/gutjnl-2021-326789. Epub 2022 Feb 1.
PubMed 35105664Berglund A, Viuff MH, Skakkebaek A, Chang S, Stochholm K, Gravholt CH. Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet J Rare Dis. 2019 Jan 14;14(1):16. doi: 10.1186/s13023-018-0976-2.
PubMed 30642344Gravholt CH, Juul S, Naeraa RW, Hansen J. Prenatal and postnatal prevalence of Turner's syndrome: a registry study. BMJ. 1996 Jan 6;312(7022):16-21. doi: 10.1136/bmj.312.7022.16.
PubMed 8555850Elsheikh M, Hodgson HJ, Wass JA, Conway GS. Hormone replacement therapy may improve hepatic function in women with Turner's syndrome. Clin Endocrinol (Oxf). 2001 Aug;55(2):227-31. doi: 10.1046/j.1365-2265.2001.01321.x.
PubMed 11531930Gravholt CH, Poulsen HE, Ott P, Christiansen JS, Vilstrup H. Quantitative liver functions in Turner syndrome with and without hormone replacement therapy. Eur J Endocrinol. 2007 Jun;156(6):679-86. doi: 10.1530/EJE-07-0070.
PubMed 17535868Ahmed S, Spence JD. Sex differences in the intestinal microbiome: interactions with risk factors for atherosclerosis and cardiovascular disease. Biol Sex Differ. 2021 May 17;12(1):35. doi: 10.1186/s13293-021-00378-z.
PubMed 34001264Org E, Mehrabian M, Parks BW, Shipkova P, Liu X, Drake TA, Lusis AJ. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes. 2016 Jul 3;7(4):313-322. doi: 10.1080/19490976.2016.1203502. Epub 2016 Jun 29.
PubMed 27355107
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Endocrine, Metabolic, Cardiovascular and Immunological Aspects of Sex Chromosome
- ClinicalTrials.gov ID
- NCT05425953
- Acronym / sponsor ID
- EMKISCA / EMKI SCA
- Conditions
- Sex Chromosome Abnormality, Klinefelter Syndrome, Turner Syndrome, Metabolic Disease, Cardiovascular Diseases, Immunologic Disease
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 320 participants (estimated)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Collaborators
- Aarhus University Hospital
- Study start
- 13 Jun 2022 (actual)
- Primary completion
- 1 May 2025 (estimated)
- Study completion
- 1 May 2025 (estimated)
- First posted
- 21 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Observational study of 160 patients with sex-chromosome abnormalities and 160 matched controls. Blood, fat, muscle, skin, buccal swaps, urine will be collected and analyzed for DNA, RNA and methylation patterns. The goal is to associated genotype and epigenetic changes with the phenotype of patients with sex-chromosome abnormalities.
Patients participate in questionaries, dexa-scan of bones, fibroscan of liver, ultra sound of testicles and blood will be analyzed for organ specific blood work as well as immunological and coagulation components.
Detailed description
Background: The most prevalent SCAs are Klinefelter syndrome (KS; 47, XXY), 47,XXX, 47,XYY and Turner syndrome (TS; 45,X) with a prevalence of 85-250, 84, 98 and 50 per 100,000 liveborn boys/girls, respectively. The majority of SCAs can suffer from a range of diseases including congenital malformations, metabolic diseases, hypergonadotropic hypogonadism and infertility, autoimmune disease and psychiatric diseases. However, the genetic mechanisms causing these phenotypes are largely unexplained. The phenotypes have been suggested to arise from alterations in DNA methylation and RNA-expression. The methylome and transcriptome in peripheral blood samples from persons with KS, 47,XXX and TS have been found to be altered in comparison with controls. These genes are now starting to be found ex. SHOX, located in the pseudo autosomal region of the X and Y chromosome, escapes X-inactivation and is therefore equivalent to the number of sex chromosomes. Altered expression of SHOX in SCAs has been associated with the altered height seen in these patients.
Hypotheses:
- The methylome and transcriptome of SCAs is altered compared to karyotypical normal female and males, and a unique methylation profile and RNA expression profile is seen for the different SCAs subgroups.
- The methylation profile and the RNA expression profile show temporal alterations.
- The DNA methylation profile and the RNA expression profile are tissue-specific.
- The phenotype and the increased risk of diseases seen in patients with SCAs are associated with the altered RNA-expression and DNA methylation profile.
Materials: Blood, fat, muscle, skin, buccal swaps, urine, will be collected from 60 klinefelter, 60 Turner syndrome patient, 20: 47, XXX and 20: 47, XYY and 80 male and female matched controls.
Methods:
Analysis of DNA-methylation using Whole Genome Bisulfite Sequencing (WGBS). Genomic DNA will be bisulfite-converted and sequenced on an Illumina Novaseq System. Sequence data pre-processors of software pipeline MethylStar. Analyzed using R.
Gene expression analysis (RNA) RNA will be cleaned and sequenced with a sequence depth of 30 million reads. Processing of sequence data using FastQC (quality control), HISAT2 (mapping) and featureCounts (gene-expression). Differences in gene-expression will be analyzed in R.
The extracted biopsies will be dissociated to singular cells RNA from these singular cells will be individually sequenced. For miRNA analysis we will isolate small non-coding RNAs and analyze these by next generation sequencing. Chromatin re-modelling can be analyzed through "footprints" left by histones on DNA-strand. Mapping of footprints along the whole X-chromosome is done using a single assay with chromatin-immunoprecipitation (CHIP) in combination med deep sequencing (chIPseq).
Genotype-Phenotype association analysis with weighted correlation network analysis (WGCNA) we will uncover the patterns in which genes behave and divide them into modules where genes react dependent of each other. These modules will afterwards be associated with the clinical data, enabling identification of the "hub" genes with the strongest associations to the phenotype.
These gene-modules, and the gene expression data itself, can furthermore be included in "deep-phenotyping" using artificial intelligence Perspectives A characterization of the methylome and transcriptome from different target tissue from patients with SCAs would not just be of significance to these patients but could lead to a larger understanding of similar diseases in patients without SCAs. Using SCAs as disease models and identify changes in DNA methylation and RNA-expression related to co-morbidity such as the metabolic syndrome, congenital heart disease or psychiatric diseases could increase the understanding of these diseases in general and potentially improve treatment in other patients groups with similar diseases.
In addition, the data collection will expand our biobank and will enable future research projects about SCAs.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Klinefelter syndrome | – | Other: No intervention other than obtaining biopsiesPatients with 47, XXY n=60 |
| Turner syndrom | – | Other: No intervention other than obtaining biopsiesPatients with 45, X n=60 |
| 47, XXX | – | Other: No intervention other than obtaining biopsiesPatients with 47, XXX n=20 |
| 47, XYY | – | Other: No intervention other than obtaining biopsiesPatients with 47, XYY n=20 |
| Male controls | – | Other: No intervention other than obtaining biopsiesMale controls n=80 |
| Female controls | – | Other: No intervention other than obtaining biopsiesFemale controls n=80 |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Study population are danish participants.
Key inclusion criteria (1 listed)
- Participants must have the sex-chromosome abnormality
Key exclusion criteria (1 listed)
- -
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| No intervention other than obtaining biopsiesBiopsies will be obtained. | Other | 47, XXX, 47, XYY, Female controls, Klinefelter syndrome, Male controls, Turner syndrom |
Primary outcome
Epigenetic changes relate to phenotype
Time frame: 2½ years
Epigenetic changes relate to phenotype
1 secondary outcome
Immunologic changes in turner syndrom
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2023.
- Background: PubMed 14752843Roulot D, Degott C, Chazouilleres O, Oberti F, Cales P, Carbonell N, Benferhat S, Bresson-Hadni S, Valla D. Vascular involvement of the liver in Turner's syndrome. Hepatology. 2004 Jan;39(1):239-47. doi: 10.1002/hep.20026.
- Background: PubMed 29438472Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebaek A. Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr Rev. 2018 Aug 1;39(4):389-423. doi: 10.1210/er.2017-00212.
- Background: PubMed 35105664de Vos WM, Tilg H, Van Hul M, Cani PD. Gut microbiome and health: mechanistic insights. Gut. 2022 May;71(5):1020-1032. doi: 10.1136/gutjnl-2021-326789. Epub 2022 Feb 1.
- Results publication: PubMed 30642344Berglund A, Viuff MH, Skakkebaek A, Chang S, Stochholm K, Gravholt CH. Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet J Rare Dis. 2019 Jan 14;14(1):16. doi: 10.1186/s13023-018-0976-2.
- Results publication: PubMed 8555850Gravholt CH, Juul S, Naeraa RW, Hansen J. Prenatal and postnatal prevalence of Turner's syndrome: a registry study. BMJ. 1996 Jan 6;312(7022):16-21. doi: 10.1136/bmj.312.7022.16.
- Results publication: PubMed 11531930Elsheikh M, Hodgson HJ, Wass JA, Conway GS. Hormone replacement therapy may improve hepatic function in women with Turner's syndrome. Clin Endocrinol (Oxf). 2001 Aug;55(2):227-31. doi: 10.1046/j.1365-2265.2001.01321.x.
- Results publication: PubMed 17535868Gravholt CH, Poulsen HE, Ott P, Christiansen JS, Vilstrup H. Quantitative liver functions in Turner syndrome with and without hormone replacement therapy. Eur J Endocrinol. 2007 Jun;156(6):679-86. doi: 10.1530/EJE-07-0070.
- Results publication: PubMed 34001264Ahmed S, Spence JD. Sex differences in the intestinal microbiome: interactions with risk factors for atherosclerosis and cardiovascular disease. Biol Sex Differ. 2021 May 17;12(1):35. doi: 10.1186/s13293-021-00378-z.
- Results publication: PubMed 27355107Org E, Mehrabian M, Parks BW, Shipkova P, Liu X, Drake TA, Lusis AJ. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes. 2016 Jul 3;7(4):313-322. doi: 10.1080/19490976.2016.1203502. Epub 2016 Jun 29.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Claus Gravholt, Prof study director
Aarhus University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Sex Chromosome Abnormality and Klinefelter Syndrome, run by University of Aarhus at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Lukas O Ridder, MD (25337447 ext. +45, Lukrid@clin.au.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Epigenetic changes relate to phenotype (time frame: 2½ years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05425953, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2023.