Novel GLDC variants causing nonketotic hyperglycinemia in Chinese patients

Objectives: Glycine decarboxylase gene (GLDC) mutations cause nonketotic hyperglycinemia (NKH). Patients of NKH usually have heterogeneous phenotypes including respiratory failure, lethargy, myoclonic jerks, and hypotonia. The excessive glycine accumulation in brain is a crucial pathogenic mechanism. Methods: We performed a clinical phenotypic analysis of two Chinese patients and conducted whole exome sequencing to detect possible pathogenic genes. Transcriptional experiments were carried out to evaluate the impact of GLDC c.862-2A>G on GLDC transcript splicing. Results: GLDC variants were identified in both patients who mainly presented with hypotonia, apnea, and lethargy patient 1 had compound heterozygous variants, which were c.334+5G>C and c.862-2A>G, while patient 2 had c.862-2A>G and c.2098C>G (p.P700A) in GLDC. Transcriptional experiments ofGLDC c.862-2A>G revealed the presence of aberrant transcripts leading to truncated protein products. Conclusions: Both patients were diagnosed with neonatal NKH. Two novel splice-site variations in GLDC, c.334+5G>C and c.862-2A>G, were identified. The c.862-2A>G variation was found in both patients and was confirmed to affect the splicing of GLDC. Our study enriched our knowledge of the genotypic and the phenotypic spectrum of NKH.