GLDC-Related Glycine Encephalopathy via the GLDC Gene

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism caused by defects in the glycine cleavage multi-enzyme system (GCS) (Hamosh et al. GeneReviews, 2002). Affected children have a large accumulation of glycine in the body resulting in various neurological symptoms. The majority of patients with glycine encephalopathy present in the neonatal period, while some patients can develop the disease in infancy. Regardless of age at onset, 20% of all affected children present with less severe phenotypes. A minority of patients have atypical outcomes. Affected neonates develop severe symptoms including progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have hypotonia, profound intellectual disability, developmental delay and intractable seizures. The atypical form has disease onset from late infancy to adulthood and the clinical outcomes range from milder features to rapidly progressive severe disease.

Glycine encephalopathy is an autosomal recessive disorder. GLDC, AMT and GCSH are the three known genes associated with the disease (Kure et al. Hum Mutat. 27:343-52, 2006). GLDC has 25 coding exons that encode glycine decarboxylase, the P-protein component of GCS. Genetic defects of GLDC account for 70-75% of glycine encephalopathy with a wide mutation spectrum including missense, nonsense, splicing site mutations, small deletion/insertions, and large deletions. Large deletions within GLDC have been reported as a major cause of the disease (Kanno et al. J Med Genet 44:e69, 2007). Although GLDC defects have been found across the whole coding region of the gene, a clustering of missense mutations in exon 19, which encodes the cofactor-binding site, has been reported (Kure et al. Hum Mutat 27:343-52, 2006).

Genetic defects of GLDC account for 70-75% of glycine encephalopathy (Hamosh et al. GeneReviews, 2002) and approximately 20% of GLDC mutant alleles are large deletions that cannot be detected by DNA sequencing of coding exons and exon-intron boundaries of the gene (Kanno et al. J Med Genet. 44:e69, 2007). Therefore, GLDC mutant alleles can be found in approximately 60% of patients with glycine encephalopathy via the current sequencing method.

This test provides full coverage of all coding exons of the GLDC gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.