Decoding the Genetic Landscape of Skeletal Diseases

Study Overview
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Brief Summary
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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
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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.

Official Title
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Decoding the Genetic Landscape of Skeletal Diseases

Conditions
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Genetic Skeletal Diseases, Skeletal Dysplasia, Molecular Causes, Skeletal Disorder

Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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What is the study measuring?
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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 |