title: The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.
abstract: 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.
authors.affiliation: Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Curtis R
authors.identifier: 0000-0002-3545-7903
authors.initials: CR
authors.lastname: Coughlin
authors.affiliation: Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Michael A
authors.identifier: 0000-0001-8983-5407
authors.initials: MA
authors.lastname: Swanson
authors.affiliation: 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.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kronquist
authors.affiliation: Service Maladies Héréditaires du Métabolisme, Centre de Biologie Est, CHU de Lyon, Lyon, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva
authors.affiliation: Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Hutchin
authors.affiliation: 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.
authors.forename: Pilar
authors.initials: P
authors.lastname: Rodríguez-Pombo
authors.affiliation: Research Group of Cancer Research and Translational Medicine, University of Oulu, Oulu, and Northern Finland Laboratory Centre Nordlab, Oulu, Finland.
authors.forename: Marja-Leena
authors.identifier: 0000-0002-6292-1388
authors.initials: ML
authors.lastname: Väisänen
authors.affiliation: 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.
authors.forename: Elaine
authors.identifier: 0000-0002-4468-8500
authors.initials: E
authors.lastname: Spector
authors.affiliation: 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.
authors.forename: Geralyn
authors.initials: G
authors.lastname: Creadon-Swindell
authors.affiliation: Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Ana M
authors.identifier: 0000-0002-2413-1721
authors.initials: AM
authors.lastname: Brás-Goldberg
authors.affiliation: PEDEGO Research Unit, Medical Research Center, Department of Clinical Genetics, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rahikkala
authors.affiliation: PEDEGO Research Unit, Medical Research Center, Department of Clinical Genetics, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Jukka S
authors.identifier: 0000-0002-8041-3205
authors.initials: JS
authors.lastname: Moilanen
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mahieu
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: 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.
authors.forename: Irene
authors.identifier: 0000-0001-7300-2515
authors.initials: I
authors.lastname: Bravo-Alonso
authors.affiliation: 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.
authors.forename: Celia
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.affiliation: 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.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.affiliation: Service Maladies Héréditaires du Métabolisme, Centre de Biologie Est, CHU de Lyon, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey-Saban
authors.affiliation: Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.|Section of Medical Genetics and Genomics, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Gunter H
authors.initials: GH
authors.lastname: Scharer
authors.affiliation: Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
mesh_terms: D000483:Alleles; D050960:Aminomethyltransferase / Q000235:genetics*; D008058:Dihydrolipoamide Dehydrogenase / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D050959:Glycine Decarboxylase Complex / Q000235:genetics*; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000235:genetics*; D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D007438:Introns; D008297:Male; D020125:Mutation, Missense
chemical_list: D050959:Glycine Decarboxylase Complex; D050841:Glycine Dehydrogenase (Decarboxylating); D008058:Dihydrolipoamide Dehydrogenase; D050960:Aminomethyltransferase; D005998:Glycine