title: Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.
abstract: OBJECTIVE
  An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency, elevated blood levels of homocysteine and methylmalonic acid, and a selective decreased synthesis of methylcobalamin in cultured fibroblasts.
  
  
  METHODS
  Exome sequencing was performed on patient genomic DNA.
  
  
  RESULTS
  Two mutations were identified in the MTHFD1 gene, which encodes a protein that catalyses three reactions involved in cellular folate metabolism. This protein is essential for the generation of formyltetrahydrofolate and methylenetetrahydrofolate and important for nucleotide and homocysteine metabolism. One mutation (c.727+1G>A) affects the splice acceptor site of intron 8. The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein. Mutations affecting this arginine have previously been shown to affect enzyme activity. Both parents carry a single mutation and an unaffected sibling carries neither mutation. The combination of two mutations in the MTHFRD1 gene, predicted to have severe consequences, in the patient and their absence in the unaffected sibling, supports causality.
  
  
  CONCLUSIONS
  This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein. This report reinforces the power of exome capture and sequencing for the discovery of novel genes, even when only a single proband is available for study.
authors.affiliation: Department of Human Genetics, Department of Medical Genetics, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Room L3-319, Montreal, QC H3G 1A4, Canada. david.watkins@mcgill.ca
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Jaya
authors.initials: J
authors.lastname: Ganesh
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Kaplan
authors.forename: Laura Dempsey
authors.initials: LD
authors.lastname: Nunez
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D000749:Anemia, Megaloblastic / Q000235:genetics; D059472:Exome; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics; D007223:Infant; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D016511:Severe Combined Immunodeficiency / Q000235:genetics
chemical_list: D015778:Minor Histocompatibility Antigens; D005492:Folic Acid; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)