Hypomethylation of Wnt signaling regulator genes in developmental language disorder

Background: Developmental language disorder (DLD) is a neurodevelopmental disorder. Considering the pivotal role of epigenetics in neurodevelopment, we examined any altered DNA methylation between DLD and control subjects. Materials & methods: We looked into genome-wide methylation differences between DLD and control groups. The findings were validated by quantitative PCR (qPCR). Results: In the DLD group, differential methylation of CpG sites was observed in the Wnt signaling regulator genes APCDD1, AMOTL1, LRP5, MARK2, TMEM64, TRABD2B, VEPH1 and WNT2B. Hypomethylation of APCDD1, LRP5 and WNT2B was confirmed by qPCR. Conclusion: This is the first report associating Wnt signaling with DLD. The findings are relevant in the light of the essential role of Wnt in myelination, and of the altered myelination in DLD. Developmental language disorder (DLD), previously called specific language impairment, is a neurodevelopmental disorder affecting approximately 7% of school-age children. Affected children fail to develop normal speech and language skills; this is a major public health concern as it adversely impacts their communication, academic and social skills. Human brain development is complex, and the accurate temporal and spatial regulation of the expression of multiple genes is essential for proper brain development. Epigenetic factors such as DNA methylation can modulate gene expression without altering the DNA sequence and are considered key regulators of the expression of genes involved in neurodevelopment. We examined any genome-wide methylation differences between children with DLD and control subjects. The findings were validated by real-time qPCR. The DLD group showed differential methylation of CpG sites in several Wnt signaling regulator genes (APCDD1, AMOTL1, LRP5, MARK2, TMEM64, TRABD2B, VEPH1, WNT2B) compared with the control group. Among these, hypomethylation of APCDD1, LRP5 and WNT2B was confirmed by qPCR. This is the first report associating Wnt signaling with DLD. The findings are relevant in the light of the essential role of Wnt in neuronal myelination and the altered myelination in DLD revealed by magnetic resonance imaging. Altered neuronal myelination is observed in developmental language disorder (DLD). Wnt signaling has a crucial role in myelination. Altered DNA methylation of Wnt signaling regulator genes could be a potential contributing factor to DLD.