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Decoding the Genetic Landscape of Skeletal Diseases (SKDLAND)

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ClinicalTrials.gov Identifier: NCT05876416
Recruitment Status : Recruiting
First Posted : May 25, 2023
Last Update Posted : May 25, 2023
Sponsor:
Collaborators:
Karolinska University Hospital
Göteborg University
Information provided by (Responsible Party):
Giedre Grigelioniene, Karolinska Institutet

Study Description
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Brief Summary:
This 5-year project aims to (1) search for genetic causes for yet unsolved congenital skeletal disorders (GSDs); (2) study consequences of the newly identified pathogenic variants in cells and in transgenic mice, (3) summarize data on natural course and complications for different GSD groups. For patients with unsolved GSD, the investigators search for molecular causes of GSDs using whole genome sequencing (WGS) and total ribonucleic acid (RNA) sequencing. Candidate gene variants are selected using genome or transcriptome sequencing data, clinical findings and screening of omics databases. Causality of the new variants is studied in cells and in transgenic mice models. Molecular and clinical findings are summarized for different GSD groups.

Condition or disease
Genetic Skeletal Diseases Skeletal Dysplasia Molecular Causes Skeletal Disorder

Detailed Description:
Genetic skeletal disorders (GSDs) are a large group of rare diseases caused by abnormalities in genes regulating skeletal development. This 5-year project aims to (1) search for genetic causes for yet unsolved congenital skeletal disorders; (2) study consequences of the newly identified pathogenic variants in cells and in transgenic mice, (3) summarize data on natural course and complications for different GSD groups. The project is a collaboration between the Dept of Clinical Genetics, Karolinska University Hospital, Lab of Clinical Genetics and Lab of Bone and Cartilage Physiology, Karolinska Institutet and Sahlgrenska Academy. In a well-characterized group of 300 GSD participants whose DNA samples were analyzed using whole genome sequencing (WGS), there are 120 study participants with unsolved diagnoses. For those participants, we search for molecular causes of GSDs using WGS and total RNA sequencing. Candidate gene variants are selected using genome or transcriptome sequencing data, clinical findings and screening of omics databases. Causality of the new variants is studied in cells and in transgenic mice models. Molecular and clinical findings are summarized for different GSD groups. Our results improve diagnostics for GSDs, advance knowledge on pathogenesis and help establishing new individual follow-up and treatment strategies for patients with GSDs. This project increases understanding of skeletal pathophysiology and will contribute to the development of novel treatment methods for skeletal diseases.
Study Design
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Study Type : Observational
Estimated Enrollment : 450 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: Decoding the Genetic Landscape of Skeletal Diseases
Actual Study Start Date : January 1, 2015
Estimated Primary Completion Date : December 31, 2026
Estimated Study Completion Date : December 31, 2026

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Outcome Measures
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Primary Outcome Measures :
  1. New gene discoveries for genetic skeletal disorders (GSDs) [ Time Frame: 2023-2028 ]
    2-3 new disease causes and disease entities identified and reported per year for GSDs.

  2. Improved knowledge regarding natural cause of rare GSDs [ Time Frame: 2023-2028 ]
    1-2 GSDs reported as small patient groups with the same condition and clinical characteristics/course.


Secondary Outcome Measures :
  1. Disease (GSD) associated traits and complications [ Time Frame: 2023-2028 ]
    The observations include internal malformations, metabolic, biochemical and growth parameters, and secondary complications.

  2. Information on disease causing variants in GSD [ Time Frame: 2023-2028 ]
    During the study we identify several novel disease causing variants in known GSD genes and report them to databases.


Biospecimen Retention:   Samples With DNA
Genomic DNA samples, primary dermal fibroblasts, RNA from blood or fibroblasts

Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Individuals of any age with congenital skeletal diseases and their healthy relatives
Criteria

Inclusion Criteria:

Clinically suspected skeletal dysplasia based on previous investigations

Abnormal height

Radiographic abnormalities of the skeleton in addition to other syndromic features

Healthy relatives of the affected study participants

Exclusion Criteria:

No radiographic data available from clinical investigations

Suspected environmental or multifactorial causes

Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT05876416


Contacts
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Contact: Giedre Grigelioniene, MD, PhD +46706287697 giedre.grigelioniene@ki.se
Contact: Hillevi Lindelöf, MD Hillevi.Lindelof@ki.se

Locations
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Sweden
Karolinska University Hospital Recruiting
Stockholm, Sweden, 17176
Contact: Giedre Grigelioniene, MD, PhD    +46706287697    Giedre.Grigelioniene@ki.se   
Contact: Hillevi Lindelöf, MD       Hillevi.Lindelof@ki.se   
Sponsors and Collaborators
Karolinska Institutet
Karolinska University Hospital
Göteborg University
Investigators
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Principal Investigator: Giedre Grigelioniene, MD, Dept Molecular Medicine and Surgery, KI
More Information
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Responsible Party: Giedre Grigelioniene, Associate Professor, MD, PhD, Karolinska Institutet
ClinicalTrials.gov Identifier: NCT05876416    
Other Study ID Numbers: 910715
2022-02647 ( Other Grant/Funding Number: Vetenskap Rådet/SRC )
First Posted: May 25, 2023    Key Record Dates
Last Update Posted: May 25, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Due to GDPR we are not able to share genomic data, but in case of joined reports anonymized clinical data such as growth parameters or information on malformations will be shared.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Osteochondrodysplasias
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Genetic Diseases, Inborn