Mendelian DisordersNCT03589079
Delineation of Novel Monogenic Disorders in the United Arab Emirates Population
An observational study of Mendelian Disorders and Genetic Disorder, run by Imperial College London Diabetes Centre at 1 site in United Arab Emirates.
Trial 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). Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Mendelian Disorders, Genetic Disorder, Novel Mutation
- What is being tested?
- Sanger and/or Next Generation Sequencing (NGS)
- How many people
- 150 participants
- Where
- 1 siteUnited Arab Emirates
- Study dates
- 1 Jan 2018to Jan 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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)
Who may be able to join
- Specific phenotype - Phenotypes of interest suggestive of an underlying novel genetic disorder:
- Unusual presentations of common disorders, e.g. with clearly defined syndromic/dysmorphic features*.
- Extreme phenotypic presentations.
- 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:
- Presence of syndromic/dysmorphic features.
Show all 13Show fewer
- Family history of similar presentations in other relative(s).
- Pattern of inheritance.
- 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:
- Exclusion of non-genetic acquired causes - e.g. those with a clear history of likely environmental cause.
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United Arab Emirates1 site, 1 recruiting
- Recruiting
Imperial College London Diabetes Centre
Abu Dhabi, 48338
Hinda Daggag, PhD, +971 2 404 0800, hdaggag@icldc.ae
About this study
Official title: Delineation of Novel Monogenic Disorders in the United Arab Emirates
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).
Read the 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.
- Conditions
- Mendelian Disorders, Genetic Disorder, Novel Mutation, Hereditary Disorder, De Novo Mutation, Inherited Disease
- Being tested
- Sanger and/or Next Generation Sequencing (NGS)
- Keywords
- Monogenic Disorder, Mendelian Disease, Single Gene Disorder, Next Generation Sequencing, Genetic testing
- Medical subject headings
- Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sanger and/or Next Generation Sequencing (NGS)Genetic
NGS panel, whole exome / genome sequencing (WES/WGS)
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Genetic: Sanger and/or Next Generation Sequencing (NGS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Novel phenotype and gene discovery
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.
Measured: through study completion, an average of 2 year
Secondary outcomes (4)
Generate new biological insights
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.
Measured: through study completion, an average of 2 year
Modifier genes of monogenic disorders
Identify modifier genes of monogenic disorders - to aid understanding of phenotypic heterogeneity of Mendelian disorders.
Measured: through study completion, an average of 2 year
Potential new therapeutic targets
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.
Measured: through study completion, an average of 2 year
Gene function and target validation
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.
Measured: through study completion, an average of 2 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jul 2018
- Study start1 Jan 2018
- Primary completionJan 2021 (estimated)
- Study completionJan 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Mendelian DisordersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Imperial College London Diabetes Centre
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Maha Barakat, PhD FRCP, Principal investigator, Imperial College London Diabetes CentreHouman Ashrafian, DPhil FRCP, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03589079
- Sponsor's protocol ID
- IREC038
- Status last verified
- Feb 2020
- First submitted
- 2 Jul 2018
- Last updated
- 12 Feb 2020
- Results posted
- No
Publications
1- Chial H. Rare Genetic Disorders: Learning About Genetic Disease Through Gene Mapping, SNPs, and Microarray Data. Nature Education 2008;1(1):192.
2- Genes and human disease. World Heath Organization 2017. Retrieved from http://www.who.int/genomics/public/geneticdiseases/en/index2.html
Ku CS, Cooper DN, Patrinos GP. The Rise and Rise of Exome Sequencing. Public Health Genomics. 2016;19(6):315-324. doi: 10.1159/000450991. Epub 2016 Nov 30.
PubMed 27898412Mefford HC. Clinical Genetic Testing in Epilepsy. Epilepsy Curr. 2015 Jul-Aug;15(4):197-201. doi: 10.5698/1535-7511-15.4.197.
PubMed 26316867de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
PubMed 23033978Della Mina E, Ciccone R, Brustia F, Bayindir B, Limongelli I, Vetro A, Iascone M, Pezzoli L, Bellazzi R, Perotti G, De Giorgis V, Lunghi S, Coppola G, Orcesi S, Merli P, Savasta S, Veggiotti P, Zuffardi O. Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform. Eur J Hum Genet. 2015 Mar;23(3):354-62. doi: 10.1038/ejhg.2014.92. Epub 2014 May 21.
PubMed 24848745
Study at a glance
From the registry record, last updated by the sponsor on 12 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Delineation of Novel Monogenic Disorders in the United Arab Emirates
- ClinicalTrials.gov ID
- NCT03589079
- Acronym / sponsor ID
- IREC038
- Conditions
- Mendelian Disorders, Genetic Disorder, Novel Mutation, Hereditary Disorder, De Novo Mutation, Inherited Disease
- Keywords
- Monogenic Disorder, Mendelian Disease, Single Gene Disorder, Next Generation Sequencing, Genetic testing
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Imperial College London Diabetes CentreUniversity, hospital or other
- Study start
- 1 Jan 2018 (actual)
- Primary completion
- Jan 2021 (estimated)
- Study completion
- Jan 2021 (estimated)
- First posted
- 17 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Monogenic Disorder | – | Genetic: Sanger and/or Next Generation Sequencing (NGS)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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- 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)
Key inclusion criteria (13 listed)
- Specific phenotype - Phenotypes of interest suggestive of an underlying novel genetic disorder:
- Family history/pedigree - Phenotype suspected to be due to a single genetic mutation (de novo or inherited) based, where available, on any of:
- 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:
- 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.
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sanger and/or Next Generation Sequencing (NGS)NGS panel, whole exome / genome sequencing (WES/WGS) | Genetic | Monogenic Disorder |
Primary outcome
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.
4 secondary outcomes
Generate new biological insights
Time frame: through study completion, an average of 2 year
Modifier genes of monogenic disorders
Time frame: through study completion, an average of 2 year
Potential new therapeutic targets
Time frame: through study completion, an average of 2 year
Gene function and target validation
Time frame: through study completion, an average of 2 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Feb 2020.
- Background1- Chial H. Rare Genetic Disorders: Learning About Genetic Disease Through Gene Mapping, SNPs, and Microarray Data. Nature Education 2008;1(1):192.
- Background2- Genes and human disease. World Heath Organization 2017. Retrieved from http://www.who.int/genomics/public/geneticdiseases/en/index2.html
- Background: PubMed 27898412Ku CS, Cooper DN, Patrinos GP. The Rise and Rise of Exome Sequencing. Public Health Genomics. 2016;19(6):315-324. doi: 10.1159/000450991. Epub 2016 Nov 30.
- Background: PubMed 26316867Mefford HC. Clinical Genetic Testing in Epilepsy. Epilepsy Curr. 2015 Jul-Aug;15(4):197-201. doi: 10.5698/1535-7511-15.4.197.
- Background: PubMed 23033978de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
- Background: PubMed 24848745Della Mina E, Ciccone R, Brustia F, Bayindir B, Limongelli I, Vetro A, Iascone M, Pezzoli L, Bellazzi R, Perotti G, De Giorgis V, Lunghi S, Coppola G, Orcesi S, Merli P, Savasta S, Veggiotti P, Zuffardi O. Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform. Eur J Hum Genet. 2015 Mar;23(3):354-62. doi: 10.1038/ejhg.2014.92. Epub 2014 May 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maha Barakat, PhD FRCP principal investigator
Imperial College London Diabetes Centre
Houman Ashrafian, DPhil FRCP principal investigator
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Mendelian Disorders and Genetic Disorder, run by Imperial College London Diabetes Centre at 1 site in United Arab Emirates.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 12 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Arab Emirates. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Hinda Daggag, PhD (+971 2 404 0800, hdaggag@icldc.ae), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Novel phenotype and gene discovery (time frame: through study completion, an average of 2 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03589079, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Feb 2020.