Genetic and functional characterization of mutations associated with neurodevelopmental disorders

Neurodevelopmental disorders include a wide spectrum of cognitive, neurological, psychiatric disorders related to growth and developmental damage of central nervous system. Although new genes/loci associated with these diseases have been identified in recent years, there is still no specific diagnosis or treatment for most patients due to genetic and phenotypic heterogeneity. Aim of study is to determine candidate gene/gene regions that may be associated with disease phenotype of patients with neurodevelopmental disorders and to reveal effect of mutation detected in ELP6 through functional studies. In genetic analysis part, WES was performed in three families, candidate genes were prioritized with bioinformatics analysis, mutations were confirmed by Sanger sequencing. A frameshift mutation (p.Trp58Phefs*10) in OCLN, detected in Family-1, suggested a potential founder effect in Turkish population. A novel homozygous missense mutation (p.Ile67Phe) in OCLN, detected in Family-2, provides additional genetic findings for BLC-PMG phenotype. A homozygous missense mutation (p.Leu118Trp) was detected in ELP6 in Family-3. In functional analysis part, punch skin biopsy samples were taken from two siblings, their mothers in Family-3 and a control individual, then primary cell cultures were prepared. Differentially expressed genes were determined by RNA-seq and the results were compatible with the function of Elongator complex. Results of tRNA modification analysis showed that Elongator-dependent tRNA modifications decrease in patients. Migration rates of patients's cells were higher than control's. Consequently, variation spectrum of OCLN gene has been expanded. ELP6 mutation has been reported for the first time in humans. Functional analysis results will contribute to understanding function of ELP6.