Identification and Characterization of Bone-related Genetic Variants in Families

Study Overview
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Brief Summary
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Identify novel genetic variants causing skeletal dysplasia in Qatari populations and to additionally develop an understanding of how those variants influence skeletal biology at a molecular and cellular level.

Detailed Description
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To identify novel genetic variants causing skeletal dysplasia in Qatari populations and to additionally develop an understanding of how those variants influence skeletal biology at a molecular and cellular level. Achieving this goal will be split into two aims: Aim 1: Perform a clinical characterization of a study group of patients with various forms of skeletal dysplasia seen in pediatric orthopedics clinic at Hamad Medical center, HMC. This will be followed by whole exome or genome sequencing and analysis to search for novel pathogenic variants responsible for the clinical presentation of these patients Aim 2: The genes and variants identified in Aim 1 will be characterized to determine their effects on osteoblast and chondrocyte differentiation and function. All the subjects will be recruited from the pool of patients seen by the Pediatric Orthopedic Consultants at the Bone and Joint Institute. Subjects will be coming to the clinic for their standard care. They will be identified during that visit as candidates for the study. They will then be told about the study by their physicians. If a patient is interested in participation, the physician will introduce the CRC to him/her who will proceed with the consent process. Consenting and the study procedures might be performed during that same visit if time allows, or in a new scheduled visit arranged at that time. This research will also involve a pedigree creation. Secondary subjects (family members or relatives) will be told about the study by the research subject. The secondary subject will be able to read a copy of the consent form, think of his participation, and if interested they will be told to contact the Investigators. A suitable time will then be arranged, by an appropriate member of the research team, for the secondary subject to visit the clinic in order to proceed with the consent process and the study procedures.

Official Title
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Identification and Characterization of Bone-related Genetic Variants in Families

Conditions
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Skeletal Dysplasia

Intervention / Treatment
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* Other: Samples With DNA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All included individuals must provide informed consent Patients identified to have a skeletal dysplasia All ethnic backgrounds are acceptable Disease must be genetic with no evident environmental cause. Evidence of Mendelian Transmission determined by fulfilling one of the following criteria: Multiple affected family members (at least first-degree relative with disease) History of consanguinity Severe disease in newborn in the absence of family history Syndromic disease in single individuals Congenital abnormality affecting major organ system(s) Mendelianized extremes of common disease (e.g. bilateral developmental dysplasia of the hip) All ages will be included Rare diseases or rare forms of known diseases Unaffected family members or relatives of the individual with the primary syndrome Exclusion Criteria: Individuals who do not consent will not be included Individuals for which a molecular diagnosis has already been established by alternative method (e.g. karyotype or known gene mutation) Diseases for which an environmental factor is most likely the cause (e.g. Traumatic bone injury or Rickets) Diseases of which late age of onset rule out Mendelian transmission Common Diseases for which late age of onset rule out Mendelian transmission (e.g.Osteoporosis)
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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Samples With DNA|After consenting, all subjects have to undergo the following procedures: Up to 25 ml of blood will be withdrawn. If for any reason, the blood sample cannot be obtained, a swab will be applied to the inside of the cheek to obtain saliva. A questionnaire will be used to collect information about individual A routine physical exam will be performed. The subject's medical record will be reviewed To well document some of the specific phenotypes and conditions, physicians might take photographs of the affected body area. For secondary subjects (relatives or family members), normal examination and routine lab tests/ imagining will be done if needed as per the related standard care.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical assessement of a study group of patients with various forms of skeletal dysplasia, followed by identification of novel pathogenic variants using whole exome/genome sequencing. | Patients will be selected for the study and will undergo: Phenotyping by a combination of clinical history taking and examination, determination of bone mass, laboratory studies, Full exome sequencing Lastly, the variants present in each exome will be determined, and these variants will be classified according to their likelihood of being pathogenic. | 2-3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical and cellular characterization of the putative causative genes. | Chondrocytes or osteoblasts will be used to measure the following: Putative gene expression in the skeletal system, How they influence osteoblast and chondrocyte differentiation how they alter the activity of the key molecular pathways governing the activity of osteoblasts and chondrocytes, | 1-2 year |