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, apn...
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Elsevier
2025-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426925000242 |
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| author | Fang Yuan Xiaozhen Song Rongrong Yin Xiaoping Lan Jingjing Sun Xiaojun Tang Wuhen Xu Shaohua Hu Man Xiao Hong Zhang Wenhao Weng Yuanfeng Zhang Shengnan Wu |
| author_facet | Fang Yuan Xiaozhen Song Rongrong Yin Xiaoping Lan Jingjing Sun Xiaojun Tang Wuhen Xu Shaohua Hu Man Xiao Hong Zhang Wenhao Weng Yuanfeng Zhang Shengnan Wu |
| author_sort | Fang Yuan |
| collection | DOAJ |
| description | 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 GLDC 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 GLDC, 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 GLDC gene. These findings highlight the pathogenic nature of a novel synonymous mutation c.1023G > A, expand the genetic spectrum of GLDC and provide crucial guidance for both the patient's clinical management and family's reproductive genetic counseling. |
| format | Article |
| id | doaj-art-8aed382b1fb848a9b87cbc027c7d4714 |
| institution | OA Journals |
| issn | 2214-4269 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj-art-8aed382b1fb848a9b87cbc027c7d47142025-08-20T02:35:51ZengElsevierMolecular Genetics and Metabolism Reports2214-42692025-06-014310120910.1016/j.ymgmr.2025.101209The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemiaFang Yuan0Xiaozhen Song1Rongrong Yin2Xiaoping Lan3Jingjing Sun4Xiaojun Tang5Wuhen Xu6Shaohua Hu7Man Xiao8Hong Zhang9Wenhao Weng10Yuanfeng Zhang11Shengnan Wu12Department of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Neonatology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Corresponding author.Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Corresponding author.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 GLDC 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 GLDC, 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 GLDC gene. These findings highlight the pathogenic nature of a novel synonymous mutation c.1023G > A, expand the genetic spectrum of GLDC and provide crucial guidance for both the patient's clinical management and family's reproductive genetic counseling.http://www.sciencedirect.com/science/article/pii/S2214426925000242GLDCGlycine cleavage enzyme systemNonketotic hyperglycinemiaSeizureSynonymous mutation |
| spellingShingle | Fang Yuan Xiaozhen Song Rongrong Yin Xiaoping Lan Jingjing Sun Xiaojun Tang Wuhen Xu Shaohua Hu Man Xiao Hong Zhang Wenhao Weng Yuanfeng Zhang Shengnan Wu The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia Molecular Genetics and Metabolism Reports GLDC Glycine cleavage enzyme system Nonketotic hyperglycinemia Seizure Synonymous mutation |
| title | The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia |
| title_full | The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia |
| title_fullStr | The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia |
| title_full_unstemmed | The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia |
| title_short | The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia |
| title_sort | precise molecular diagnosis of novel gldc compound heterozygous variants highlights the benefits for a chinese family with nonketotic hyperglycinemia |
| topic | GLDC Glycine cleavage enzyme system Nonketotic hyperglycinemia Seizure Synonymous mutation |
| url | http://www.sciencedirect.com/science/article/pii/S2214426925000242 |
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