Genetic Skeletal Diseases, Molecular Causes, Skeletal Disorder, Skeletal Dysplasia
Conditions
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.
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.
Interventions
None listed
Sponsors
Karolinska University Hospital
Göteborg University
Karolinska Institutet
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| New gene discoveries for genetic skeletal disorders (GSDs) | 2023-2028 | 2-3 new disease causes and disease entities identified and reported per year for GSDs. |
| Improved knowledge regarding natural cause of rare GSDs | 2023-2028 | 1-2 GSDs reported as small patient groups with the same condition and clinical characteristics/course. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease (GSD) associated traits and complications | 2023-2028 | The observations include internal malformations, metabolic, biochemical and growth parameters, and secondary complications. |
| Information on disease causing variants in GSD | 2023-2028 | During the study we identify several novel disease causing variants in known GSD genes and report them to databases. |
Countries
Sweden
Contacts
Primary ContactGiedre Grigelioniene, MD, PhD
Backup ContactHillevi Lindelöf, MD
Outcome results
None listed