Delineation of Novel Monogenic Disorders in the United Arab Emirates Population

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).

Study Overview

• Status: Unknown
• Conditions: Mendelian Disorders; Genetic Disorder; Novel Mutation; Hereditary Disorder; De Novo Mutation; Inherited Disease; Single-Gene Defects
• Intervention / Treatment: 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.

• Study Type: Observational
• Enrollment (Anticipated): 150

Contacts and Locations

Study Locations

• United Arab Emirates
  • Abu Dhabi, United Arab Emirates, 48338
    • Recruiting
    • Imperial College London Diabetes Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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)

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

1

Cohorts and Interventions

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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	through study completion, an average of 2 year

Collaborators and Investigators

• Sponsor: Imperial College London Diabetes Centre
• Investigators: Principal Investigator: Houman Ashrafian, DPhil FRCP, University of Oxford

Publications and helpful links

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

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Anticipated): January 1, 2021
• Study Completion (Anticipated): January 1, 2021

Study Registration Dates

• First Submitted: July 2, 2018
• First Submitted That Met QC Criteria: July 16, 2018
• First Posted (Actual): July 17, 2018

Study Record Updates

• Last Update Posted (Actual): February 12, 2020
• Last Update Submitted That Met QC Criteria: February 11, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Genetic testing; Monogenic Disorder; Mendelian Disease; Single Gene Disorder; Next Generation Sequencing
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Genetic Diseases, Inborn
• Other Study ID Numbers: IREC038

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No