Decoding the Genetic Landscape of Skeletal Diseases (SKDLAND)

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.

Study Overview

• Status: Recruiting
• Conditions: Skeletal Dysplasia; Skeletal Disorder; Genetic Skeletal Diseases; Molecular Causes

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 Type: Observational
• Enrollment (Estimated): 450

Contacts and Locations

• Study Contact: Name: Giedre Grigelioniene, MD, PhD; Phone Number: +46706287697; Email: Giedre.Grigelioniene@ki.se
• Study Contact Backup: Name: Hillevi Lindelöf, MD; Email: Hillevi.Lindelof@ki.se

Study Locations

• Sweden
  • Stockholm, Sweden, 17176
    • Recruiting
    • Karolinska University Hospital
    • Contact: Giedre Grigelioniene, MD, PhD; Phone Number: +46706287697; Email: Giedre.Grigelioniene@ki.se
    • Contact: Hillevi Lindelöf, MD; Email: Hillevi.Lindelof@ki.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Individuals of any age with congenital skeletal diseases and their healthy relatives

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
New gene discoveries for genetic skeletal disorders (GSDs)	2-3 new disease causes and disease entities identified and reported per year for GSDs.	2023-2028
Improved knowledge regarding natural cause of rare GSDs	1-2 GSDs reported as small patient groups with the same condition and clinical characteristics/course.	2023-2028

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease (GSD) associated traits and complications	The observations include internal malformations, metabolic, biochemical and growth parameters, and secondary complications.	2023-2028
Information on disease causing variants in GSD	During the study we identify several novel disease causing variants in known GSD genes and report them to databases.	2023-2028

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Karolinska University Hospital; Göteborg University
• Investigators: Principal Investigator: Giedre Grigelioniene, MD,, Dept Molecular Medicine and Surgery, KI

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: April 16, 2023
• First Submitted That Met QC Criteria: May 16, 2023
• First Posted (Actual): May 25, 2023

Study Record Updates

• Last Update Posted (Actual): May 25, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias
• Other Study ID Numbers: 910715; 2022-02647 (Other Grant/Funding Number: Vetenskap Rådet/SRC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD 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.

Drug and device information, study documents

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