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Genet Med. 2017 Jan;19(1):104-111. doi: 10.1038/gim.2016.74. Epub 2016 Jun 30.

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

Author information

Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Molecular Genetics Laboratory, Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
Service Maladies Héréditaires du Métabolisme, Centre de Biologie Est, CHU de Lyon, Lyon, France.
Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham, UK.
Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), CBM-SO, (UAM-CISC), Centro de Investigación en Red de Enfermedades Raras (CIBERER), IDIPAZ, Universidad Autónoma Madrid, Madrid, Spain.
Research Group of Cancer Research and Translational Medicine, University of Oulu, Oulu, and Northern Finland Laboratory Centre Nordlab, Oulu, Finland.
PEDEGO Research Unit, Medical Research Center, Department of Clinical Genetics, Oulu University Hospital and University of Oulu, Oulu, Finland.
Center for Human Genetics, University of Leuven, Leuven, Belgium.
Section of Medical Genetics and Genomics, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.



The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH).


Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database.


In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000.


The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.

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