Harnessing genomic technologies to accelerate the discovery of the molecular basis of neurodevelopmental disorders in Palestinian communitie

The overarching objective of this proposal is to establish and cement my collaborative relationship with the Crosby/Baple Rare Disease research group at the University of Exeter and to develop the knowledge, skills and infrastructure to enable novel gene discovery for neurodevelopmental disease in Palestinian communities.

In doing this, this project will advance scientific and medical knowledge of neurodevelopmental molecules and biological pathways, while providing impacting diagnostic and clinical management benefits for participating families.

This project has immense potential to seed future focussed studies to investigate the biomolecular disease mechanisms identified.

It will also provide a solid platform for project expansion enabling a long-term patient and family recruitment program for continued discoveries, positioning the applicant make an impacting and unique contribution to the field of neurodevelopmental disease.

Inherited neurodevelopmental disorders present in rural Palestinian communities often derive from the enrichment of specific founder gene variants due to community marriage patterns and historical ancestral population bottlenecks, followed by population expansion. Together with the typical large family size, this enables greatly empowered genetic studies.

Over recent months, ethical approval has been obtained and, an Material Transfer Agreement established with the University of Exeter Medical School.

I have also identified >50 extended Palestinian families with individuals affected with moderate-profound developmental delay/intellectual disability with or without additional syndromic features, phenotyped by myself and/or local clinicians with support from Prof Turnpenny and Dr Baple (both are experienced Clinical Geneticists).

In these families, the clinical phenotype and investigations undertaken to date are not suggestive of a recognisable disorder.

DNA is available from affected individuals from each branch of the extended family, unaffected siblings and parents where living.

Genomic Studies to be undertaken collaboratively in Exeter: Given the extensive genetic heterogeneity of inherited neurodevelopmental disorders, and as genetic studies have not yet been undertaken of the families identified, a proportion of the conditions will likely relate to already known genetic causes.

Genomic findings will enable additional genotype-phenotype correlations to be drawn, while providing important diagnostic/management benefits for families.

However, an important proportion (estimated likely to entail ~35% of families, from my Exeter collaborators previous experiences of similar previously unstudied community research programs) will likely relate to new genes, enabling the identification of important new biomolecular pathways.

Genomic studies will involve whole exome/genome sequencing depending on the nature of the disorder and family structure.

For maximal cost-effectiveness a single affected individual from each family will be investigated initially, using state of the art DNA sequencing facilities via the Exeter in-house sequencing/molecular services (Illumina NovaSeq, NextSeq and PacBio) and customised in-house bioinformatics pipelines.

The sequencing will be undertaken before my visit, in order to maximise the time available for me to undertake analysis of the data.

Follow-up of new candidate genes will be via GeneMatcher and information exchange agreements between Prof Crosby/Dr Baple with large scale exome sequencing centres (Baylor- Prof Lupski, King Faisal Hospital – Prof Alkuraya, Wellcome Trust Sanger Institute DDD Study- Prof Hurles) and 100,000 Genome Project GeCIPs, alongside cosegregation/regional control studies to confirm likely causality