Browsing by Author "Doagu, Fatma"

Intellectual disability (ID) is a clinically diverse and genetically heterogeneous disorder characterized by central nervous system defects of varying severity resulting in substantial impairment of intellectual and adaptive functioning as expressed in conceptual (IQ<70), social and practical adaptive skills diagnosed before 18 years of age. The condition is referred to as non-syndromic when ID is the only clinical feature and syndromic when ID is accompanied by specific other features, for example, Down syndrome. Intellectual disability is one of the largest unsolved problems of health care with a prevalence of 2-3% in the population. There is a 30-40% excess of male versus female patients in ID which refers to over-representation of X chromosomal defects causing ID. In this study, exome sequencing of the X chromosome was applied in order to identify genes and their mutations in two Finnish families with intellectual disability of unknown cause. The mutations were identified using Agilent Sure select array that covers almost 93% of the coding region of the chromosome. Exome sequencing resulted in 11 variations in total. Segregation of these variants was studied using PCR, ExoSAP-IT purification protocol and BigDye® Terminator v3.1 Cycle Sequencing Kit. Eventually, two novel mutations were identified: one for each family. Both mutations reside in genes that have previously been shown to cause X-linked intellectual disability. Both of the mutations were absent in over 120 control DNA samples. In one family with three affected males, a novel splice mutation was identified in discs large homolog 3 (DLG3), which encodes synapse-associated protein 102 (SAP102). The mutation is located at the splice site in intron 1 (500+1 G>C) and its effect on protein function needs to be analyzed at the RNA-level using cDNA-sequencing. The clinical phenotype of the three affected brothers is mild to moderate intellectual disability. In the other family with three severely affected male patients, a novel mutation in exon 12 was identified on glutamate receptor, ionotropic, AMPA 3 (GRIA3) resulting in amino acid glycine (GGG) changing to arginine (CGG) at codon 630 (G630R). GRIA3 belongs to AMPA receptors implicated in the regulation of several biological processes. Our findings elucidate the power of exome sequencing in the diagnosis of rare, genetically heterogeneous disorders like intellectual disability. The results obtained will help in assessing the prognosis of the disease, in estimating the risk of the disorder to other family members, and in facilitating the development of future therapies for these devastating disorders. The results also further confirm the role of DLG3 and GRIA3 in human cognitive development.