Work

Severe nonketotic hyperglycinaemia due to a synonymous variant

Year: 2025

Type: article

Abstract: Nonketotic hyperglycinaemia (NKH) is an autosomal recessive neurometabolic disorder resulting from deficient glycine cleavage system activity, causing severe neurological impairment. While NKH is typically associated with pathogenic variants in glycine decarboxylase ( GLDC ) or aminomethyltransferase, the role of synonymous variants remains uncertain. To date, no cases of NKH caused by GLDC homozygous synonymous variants have been reported. Herein, a female infant born to consanguineous parents who developed refractory seizures, progressing to infantile epileptic spasms syndrome at 2 months is reported. Initial genetic testing identified a homozygous synonymous GLDC variant (c.1023G > A, p.Val341=), previously classified as “likely benign” in ClinVar (variation identification number: 1108119). Minigene splicing analysis revealed that the c.1023G > A variant caused a 38-base pair deletion in exon 7 (r.1021_1058del), Given the phenotypic characteristics of the child, we predict that this may resulting in a frameshift mutation (p.Val341ArgfsTer56) and a truncated protein. This functional evidence confirmed the pathogenicity of the variant.

Source: Molecular Genetics and Metabolism Reports

DOI: 10.1016/j.ymgmr.2025.101268

Authors: Ping Pang, Lin Wan, Yan Liang, Xia Zhao, Guang Yang

Institutions: Chinese PLA General Hospital, First Affiliated Hospital of Chinese PLA General Hospital, Chinese People's Liberation Army, Shenzhen Children's Hospital

Language: English

Topic: Metabolism and Genetic Disorders

Subfield: Clinical Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,400