Investigation of the molecular basis of inherited neurodevelopmental disorders in Palestinian communities

Abstract

Neurodevelopmental disorders (NDDs) comprise an expansive group of clinically and genetically heterogenous conditions affecting 3% of children worldwide. Identifying the precise genetic causes of these disorders is crucial for aiding diagnosis, improving healthcare provision and exploring potential new therapeutic approaches. This thesis details genomic studies undertaken in three extended Palestinian families with individuals affected by distinct forms of inherited neurodevelopmental disorder. Chapter 3.1 describes the discovery of a homozygous likely pathogenic gene variant in PTPN23 as the likely cause of autosomal recessive complex HSP in family 1. A review of published candidate pathogenic PTPN23 variants determined that a number of these were likely benign and revealed that pathogenic biallelic PTPN23 variants cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, highlighting the importance of including PTPN23 in HSP gene testing panels. Chapter 3.2 documents investigations undertaken in family 2, which identified a homozygous missense variant in TECPR2 as the likely cause of the syndromic neurodevelopmental disorder affecting two siblings. The results of this study illustrate the difficulties associated with diagnostic classification of missense variants identified in communities under-represented in publicly accessible genomic databases. Chapter 3.3 details studies investigating homozygous variants in two genes, AGAP6 and MOB3A, that both segregated with the neurodevelopmental disorder in family 3. The ultimate confirmation of either gene as the cause of disease will entail a new disease gene discovery. Together the studies described in this thesis improve knowledge of Palestinian founder variants associated with neurogenetic disorders, greatly aiding the provision of targeted diagnostic testing and clinical management for Palestinian families affected by this group of conditions