Delineation of Novel Monogenic Disorders in the United Arab Emirates Population
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|ClinicalTrials.gov Identifier: NCT03589079|
Recruitment Status : Recruiting
First Posted : July 17, 2018
Last Update Posted : July 17, 2018
|Condition or disease||Intervention/treatment|
|Mendelian Disorders Genetic Disorder Novel Mutation Hereditary Disorder De Novo Mutation Inherited Disease Single-Gene Defects||Genetic: Sanger and/or Next Generation Sequencing (NGS)|
Monogenic disorders result from a single defective gene and are inherited according to Mendel's Laws (Mendelian disorders). Such gene defects arise from a mutation that can either be inherited or occur spontaneously; both may occur in the absence of a previous family history. Inherited mutations can be dominant or recessive, and autosomal or sex-linked. According to WHO, although individually rare, collectively monogenic disorders affect millions of people worldwide. Currently, over 10,000 human diseases are estimated to be monogenic. Until recently the identification of the genetic causes, especially of extremely rare phenotypes, has not been possible or cost effective due to the scientific challenges of identifying causative mutations through linkage analysis. The advent of cost effective next generation sequencing now facilitates the identification of all rare variants across the whole genome, in turn allowing mutation identification in small families and, if de novo, even in single cases.
The clinical application of single gene sequencing potentially provides tangible benefits to patients, informing diagnosis and prognosis, and may guide treatment choice. Next generation sequencing (NGS) panels sequence multiple genes in parallel and are now entering the clinical domain. NGS provides significant advantages over single gene sequencing for conditions which are genetically heterogeneous, such as the epilepsies. However, as more genes are included in an NGS panel, the possibility of incidental findings rises significantly, with associated challenges in result interpretation. Since many conditions are phenotypically as well as genetically heterogeneous, acquisition of detailed phenotypic information is essential for meaningful interpretation of NGS results.
Monogenic (Mendelian) disorders have historically provided the clearest means of elucidating human gene function. The linkage of a rare DNA variant to altered protein function or dose to discrete phenotype has important implications for fundamental biology, monogenic disease pathogenesis, complex traits, diagnostics and therapy. By representing the most readily interpretable component of human genetics in defining a clear, high-penetrance phenotype arising from alteration in function of a single gene, study of monogenic disorders can identify the genetic basis for novel or existing phenotypes and provide insights into non-redundant biological pathways that may inform therapeutic targeting for both the specific rare variant and common diseases. Accordingly the primary purpose of this programme is to identify novel monogenic phenotypes and discover underlying causal genetic variants by genetic sequencing in families across the UAE.
|Study Type :||Observational|
|Estimated Enrollment :||150 participants|
|Official Title:||Delineation of Novel Monogenic Disorders in the United Arab Emirates|
|Actual Study Start Date :||January 1, 2018|
|Estimated Primary Completion Date :||January 2020|
|Estimated Study Completion Date :||January 2020|
Participants exhibiting clinical phenotypes suggestive of an underlying novel monogenic disorder, with/without the presence of familial recurrence of the phenotype and/or parental consanguinity will be included. Sanger and/or Next generation Sequencing (NGS) - Panel/WES/WGS approaches will be used to facilitate identification of de novo/inherited variants in the child/proband.
Genetic: Sanger and/or Next Generation Sequencing (NGS)
NGS panel, whole exome / genome sequencing (WES/WGS)
- Novel phenotype and gene discovery [ Time Frame: through study completion, an average of 2 year ]
Identification and characterisation of novel monogenic phenotypes from specific pedigrees.
Unbiased identification of novel, rare disease-causing genes through application of genetic sequencing methodologies to new or established phenotypes.
- Generate new biological insights [ Time Frame: through study completion, an average of 2 year ]Obtain insights into the pathological mechanisms (known or new downstream disease pathways) underlying monogenic disease and more broadly to common/complex diseases, in addition to fundamental insights concerning physiological gene function.
- Modifier genes of monogenic disorders [ Time Frame: through study completion, an average of 2 year ]Identify modifier genes of monogenic disorders - to aid understanding of phenotypic heterogeneity of Mendelian disorders.
- Potential new therapeutic targets [ Time Frame: through study completion, an average of 2 year ]Identify potential new therapeutic targets - leverage these insights to identify robust, genetically-defined potential molecular and cellular drug targets (related to the primary gene and/or modifier genes) for the treatment of rare (orphan) and/or common disease.
- Gene function and target validation [ Time Frame: through study completion, an average of 2 year ]Where feasible, determine the functional impact of identified pathogenic variants and validate disease mechanism-based targets through the use of pre-clinical (in vitro/in vivo) and/or early human experimental studies.
Biospecimen Retention: Samples With DNA
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03589079
|Contact: Hinda Daggag, PhD||+971 2 404 email@example.com|
|United Arab Emirates|
|Imperial College London Diabetes Centre||Recruiting|
|Abu Dhabi, United Arab Emirates, 48338|
|Contact: Hinda Daggag, PhD +971 2 404 0800 firstname.lastname@example.org|
|Principal Investigator:||Maha Barakat, PhD FRCP||Imperial College London Diabetes Centre|
|Principal Investigator:||Houman Ashrafian, DPhil FRCP||University of Oxford|