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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
Sponsor:
Information provided by (Responsible Party):
Imperial College London Diabetes Centre

Tracking Information
First Submitted Date July 2, 2018
First Posted Date July 17, 2018
Last Update Posted Date July 17, 2018
Actual Study Start Date January 1, 2018
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: July 16, 2018)
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.
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: July 16, 2018)
  • 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.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Delineation of Novel Monogenic Disorders in the United Arab Emirates Population
Official Title Delineation of Novel Monogenic Disorders in the United Arab Emirates
Brief Summary The study aims to identify novel monogenic phenotypes from specific pedigrees and discover the underlying causal genetic variant using genetic sequencing (Sanger and/or Next Generation Sequencing - Panel/WES/WGS) methodologies in families across the United Arab Emirates (UAE).
Detailed Description

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
Study Design Observational Model: Cohort
Time Perspective: Cross-Sectional
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
DNA will be extracted from collected blood samples for genetic analysis
Sampling Method Probability Sample
Study Population

Participants will be exhibiting clinical phenotypes suggestive of an underlying novel monogenic disorder, with/without the presence of familial recurrence of the phenotype and/or parental consanguinity.

Pedigrees of particular interest (in order of preference) will include:

  • Consanguineous families, ideally where one or more family member is affected
  • De novo based - i.e. trios of proband and both parents, where only the proband exhibits the phenotype
  • Autosomal recessive
  • Autosomal dominant, albeit with a large kindred (e.g. ideally 6-8 affected members across 2-3 generations)
Condition
  • Mendelian Disorders
  • Genetic Disorder
  • Novel Mutation
  • Hereditary Disorder
  • De Novo Mutation
  • Inherited Disease
  • Single-Gene Defects
Intervention Genetic: Sanger and/or Next Generation Sequencing (NGS)
NGS panel, whole exome / genome sequencing (WES/WGS)
Study Groups/Cohorts Monogenic Disorder
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.
Intervention: Genetic: Sanger and/or Next Generation Sequencing (NGS)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: July 16, 2018)
150
Original Estimated Enrollment Same as current
Estimated Study Completion Date January 2020
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Specific phenotype - Phenotypes of interest suggestive of an underlying novel genetic disorder:

    1. Unusual presentations of common disorders, e.g. with clearly defined syndromic/dysmorphic features*.
    2. Extreme phenotypic presentations.
    3. Entirely novel, previously undefined phenotypes.
  • Family history/pedigree - Phenotype suspected to be due to a single genetic mutation (de novo or inherited) based, where available, on any of:

    1. Presence of syndromic/dysmorphic features.
    2. Family history of similar presentations in other relative(s).
    3. Pattern of inheritance.
    4. Parental consanguinity.
  • Clinical interpretation - Where available (i.e. not mandatory but will increase confidence in suitability), the presence of clinical and/or investigation results consistent with a novel inherited/monogenic disorder:

    1. Exclusion of non-genetic acquired causes - e.g. those with a clear history of likely environmental cause.
    2. Genotype negative for known genes underlying the disorder/phenotype.
  • Consent - Participant (or parent/legal guardian if aged under 18 years) willing and able to give informed consent for participation in the study as the proband (male/female), parent in a trio or extended family member.

Exclusion Criteria:

  • Participant or their legal guardian/legal representative is unwilling or unable to give informed consent. In cases where a potential child participant has capacity to assent but refuses to participate, the will of the child will be respected.
  • Participant who has already undergone genotyping/panel/laboratory testing (e.g. for known inborn errors of metabolism) and has a defined/diagnosed genetic condition.
Sex/Gender
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers No
Contacts
Contact: Hinda Daggag, PhD +971 2 404 0800 hdaggag@icldc.ae
Listed Location Countries United Arab Emirates
Removed Location Countries  
 
Administrative Information
NCT Number NCT03589079
Other Study ID Numbers IREC038
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Imperial College London Diabetes Centre
Study Sponsor Imperial College London Diabetes Centre
Collaborators Not Provided
Investigators
Principal Investigator: Maha Barakat, PhD FRCP Imperial College London Diabetes Centre
Principal Investigator: Houman Ashrafian, DPhil FRCP University of Oxford
PRS Account Imperial College London Diabetes Centre
Verification Date July 2018