Delineation of Novel Monogenic Disorders in the United Arab Emirates Population

NCT03589079 | Unknown

• 1 other identifier: IREC038
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 1

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).

Conditions

Mendelian Disorders; Genetic Disorder; Novel Mutation; Hereditary Disorder; De Novo Mutation; Inherited Disease; Single-Gene Defects

Keywords

Monogenic Disorder; Mendelian Disease; Single Gene Disorder; Next Generation Sequencing; Genetic testing

Outcome Measures

Primary Outcomes (1)

• 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.

  through study completion, an average of 2 year

Secondary Outcomes (4)

• Generate new biological insights

  through study completion, an average of 2 year

• Modifier genes of monogenic disorders

  through study completion, an average of 2 year

• Potential new therapeutic targets

  through study completion, an average of 2 year

• Gene function and target validation

  through study completion, an average of 2 year

Study Arms (1)

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)

Interventions

Sanger and/or Next Generation Sequencing (NGS) GENETIC

NGS panel, whole exome / genome sequencing (WES/WGS)

Monogenic Disorder

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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)

You may qualify if:

• 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.
• 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:
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Imperial College London Diabetes Centre: lead

Study Sites (1)

Imperial College London Diabetes Centre

Abu Dhabi, 48338, United Arab Emirates

RECRUITING

Related Publications (6)

• 1- Chial H. Rare Genetic Disorders: Learning About Genetic Disease Through Gene Mapping, SNPs, and Microarray Data. Nature Education 2008;1(1):192.

  BACKGROUND

• 2- Genes and human disease. World Heath Organization 2017. Retrieved from http://www.who.int/genomics/public/geneticdiseases/en/index2.html

  BACKGROUND

• 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.

  PMID: 27898412 BACKGROUND

• Mefford HC. Clinical Genetic Testing in Epilepsy. Epilepsy Curr. 2015 Jul-Aug;15(4):197-201. doi: 10.5698/1535-7511-15.4.197.

  PMID: 26316867 BACKGROUND

• de 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.

  PMID: 23033978 BACKGROUND

• Della 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.

  PMID: 24848745 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

DNA will be extracted from collected blood samples for genetic analysis

MeSH Terms

Conditions

Genetic Diseases, Inborn

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Maha Barakat, PhD FRCP

  Imperial College London Diabetes Centre

  PRINCIPAL INVESTIGATOR

• Houman Ashrafian, DPhil FRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hinda Daggag, PhD

CONTACT

+971 2 404 0800; hdaggag@icldc.ae

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2018
• First Posted: July 17, 2018
• Study Start: January 1, 2018
• Primary Completion: January 1, 2021
• Study Completion: January 1, 2021
• Last Updated: February 12, 2020

Record last verified: 2020-02

Locations

AE (1)