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Approved Research

Phenome-wide association study (PheWAS) on Rett syndrome genes

Principal Investigator: Professor Murim Choi
Approved Research ID: 69079
Approval date: January 11th 2021

Lay summary

Rett syndrome (RTT) is a devastating neurodevelopmental disorder, typically features stereotypy, gait, and ablated social interaction and linguistic ability. A large portion of the patients also experience normal development in the first 6-18 months after birth followed by sudden developmental halt or regression. MECP2 has been implicated as a main gene in the generation of the disease, whereas in a smaller portion, other genes, such as FOXG1, CDKL5, and GABBR2 are also responsible for the disease when mutated. According to the databases of MECP2 variants, many variants are non-pathogenic (ClinVar: 655/1,086 = 60.3%, and RettBASE: 390/925 = 42.2% are being categorized as non-pathogenic), and it is not yet clarified whether these variants of unclear significances (VUS) are able to alter gene function. Also it is still unclear whether the RTT genes are important in determining normal neurodevelopment and brain function.

To address these questions, we propose to perform PheWAS using the UK Biobank (UKB) database. We will first extract variants in these four RTT-associated genes and divide the UKB cohort to compare phenotypic profiles between the carriers and non-carriers. This initial result will be combined with RTT patient cohorts that we maintain in our institution to construct a spectrum of individuals with variable phenotype and genotypes. We believe that this study will uncover novel function of RTT genes in brain development and function in apparently normal individuals.