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).

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.

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.

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)