Working… Menu

Delineation of Novel Monogenic Disorders in the United Arab Emirates Population

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03589079
Recruitment Status : Recruiting
First Posted : July 17, 2018
Last Update Posted : July 17, 2018
Information provided by (Responsible Party):
Imperial College London Diabetes Centre

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).

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)

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.

Layout table for study information
Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
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

Resource links provided by the National Library of Medicine

Group/Cohort Intervention/treatment
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.
Genetic: Sanger and/or Next Generation Sequencing (NGS)
NGS panel, whole exome / genome sequencing (WES/WGS)

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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
DNA will be extracted from collected blood samples for genetic analysis

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03589079

Layout table for location contacts
Contact: Hinda Daggag, PhD +971 2 404 0800

Layout table for location information
United Arab Emirates
Imperial College London Diabetes Centre Recruiting
Abu Dhabi, United Arab Emirates, 48338
Contact: Hinda Daggag, PhD    +971 2 404 0800   
Sponsors and Collaborators
Imperial College London Diabetes Centre
Layout table for investigator information
Principal Investigator: Maha Barakat, PhD FRCP Imperial College London Diabetes Centre
Principal Investigator: Houman Ashrafian, DPhil FRCP University of Oxford

Layout table for additonal information
Responsible Party: Imperial College London Diabetes Centre Identifier: NCT03589079     History of Changes
Other Study ID Numbers: IREC038
First Posted: July 17, 2018    Key Record Dates
Last Update Posted: July 17, 2018
Last Verified: July 2018
Keywords provided by Imperial College London Diabetes Centre:
Monogenic Disorder
Mendelian Disease
Single Gene Disorder
Next Generation Sequencing
Genetic testing
Additional relevant MeSH terms:
Layout table for MeSH terms
Genetic Diseases, Inborn
Pathologic Processes