The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NHK), is a rare inherited disease caused by an inborn error of glycine metabolism, resulting in elevated glycine concentration in plasma and cerebrospinal fluid. Clinical manifestations mainly include varying degrees of hypotonia, apneic episodes, epilepsy, psychomotor delay during the neonatal period or early infancy. Biallelic variants in <i>GLDC</i> account for up to 80 % of classical NKH cases. Here we describe the clinical, biochemical, and molecular characteristics of two Chinese siblings with severe NHK. Their phenotypes included severe symptoms in neonatal period, seizures, and psychomotor delay. The siblings carry novel compound heterozygous variants in <i>GLDC</i>, c.1740C > G (p.His580Gln) and c.1023G > A (p.Val341=). Based on previous literature reports and pathogenicity prediction, the c.1740C > G (p.His580Gln) variant is classified as likely pathogenic. By minigene analysis, we confirmed the synonymous mutation c.1023G > A (p.Val341=) led to abnormal splicing, with 38 bp missing in exon 7 in the <i>GLDC</i> gene. These findings highlight the pathogenic nature of a novel synonymous mutation c.1023G > A, expand the genetic spectrum of <i>GLDC</i> and provide crucial guidance for both the patient's clinical management and family's reproductive genetic counseling.