Identification and bioinformatics analysis of a novel mutation in PLA2G6 gene in a patient with neurodegenerative disorder

PLA2G6-associated neurodegeneration disorders are a group of conditions that result from mutations in the PLA2G6 gene. These disorders can cause a range of symptoms affecting the brain and nervous system, such as movement problems, cognitive decline, and vision loss. In this case, Whole Exome Sequencing (WES) was conducted on a 9-year-old boy born to consanguineous parents, who have an increased risk of passing on recessive genetic disorders. Although the boy did not exhibit any clinical symptoms until he was seven months old, his condition deteriorated severely by the age of two, rendering him unable to sit or move around, and he did not develop the ability to speak. DNAs were extracted from the blood samples of the proband (the 9-year-old boy) and his parents. The proband's DNA was sequenced using WES to identify potential disease-causing mutations. To confirm the WES findings, PCR-Sanger sequencing analysis was performed on the DNAs obtained from the proband (the 9-year-old boy) and his parents. The effect of the mutation on the protein structure was studied using the I-TASSER web-tool, which uses computational methods to predict protein structure and function based on amino acid sequences. The analysis of WES data revealed a homozygous dinucleotide TG insertion at position c.1362-1363 in exon 10 of the PLA2G6 gene (NC_000022.11(NM_003560.4):c.1362_1363insTG). This insertion introduced a premature stop codon at position 455 (p.Met455Ter) in the protein sequence. The validation of the WES results using PCR-Sanger sequencing confirmed the presence of the mutation in the proband and revealed that both parents were carriers of the mutation. The premature stop codon, located 65 nucleotides before the exon-junction complex, is likely to be detected by the nonsense-mediated mRNA decay (NMD) pathway, leading to the degradation of the mRNA. The use of the I-TASSER web-tool further supported the findings by demonstrating significant structural and functional changes in the mutant protein. Observing a very severe phenotype in our case supports the idea that the mutation was highly deleterious.