Intellectual disability (ID) is devastating condition which is defined using three criteria: reduced intellectual ability, deficit in two or more adaptive behaviours, and diagnosis before the age of 18 years. ID can have various causes, but genetic factors are thought to be responsible for up to 50% of cases. ID is a heterogeneous and complex disorder, and more than 800 genes have been implicated in its pathology. Schizophrenia (SZ) is another complex neurodevelopmental condition that also affects the brain and has a partially overlapping genetic basis with ID. This thesis describes work carried out into the genetic basis of ID and SZ.
The ID project was focused on ID in consanguineous families recruited in Oman. Next generation sequencing allowed the identification of apparently causative mutations in three out of the six families recruited. The mutations are all novel, although some of them occur in previously associated ID genes. The known ID genes in which novel mutations were identified are TUSC3 (NM_006765: exon2:c.222delA, p.R74 fs) and NHS (NM_198270:exon8: c.C4385G, p.S1462C). A novel LHFPL5 variant (NM_182548:exon2:c.T575C, p.L192P) was also identified in an ID family with hearing loss. In one ID family, mutations in two genes not previously associated with ID were found: ANKRD2 (NM_001129981:exon8:c.C883T, p.R295W) and PDZD8 (PDZD8:NM_173791: exon5:c.2197_2200del, p.733_734del).
The SZ project was focused on two SZ families recruited in the UK. Preliminary work on these families had suggested the involvement of homozygosity for genetic variants in the DFNB31 gene and in a region of Chr13q in the pathogenesis of schizophrenia. Further experiments to validate the initial findings included testing the overexpression of the DFNB31 variant (R450C) in the SH-SY5Y cell line, pull-down assay and transcript analysis of the genes located at Chr13q.
Identification of the causative mutated gene is an important step in understanding more about the biology of ID and SZ. It also facilitates carrier testing and genetic counselling, and identifies a pathway for potential therapeutic intervention.
