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Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband
  1. David Watkins1,
  2. Jeremy A Schwartzentruber2,
  3. Jaya Ganesh3,
  4. Jordan S Orange4,
  5. Bernard S Kaplan5,
  6. Laura Dempsey Nunez1,
  7. Jacek Majewski1,2,
  8. David S Rosenblatt1,6,7
  1. 1Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  2. 2McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
  3. 3Section of Metabolic Disease, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  4. 4Division of Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  5. 5Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  6. 6Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada
  7. 7MUHC Research Institute, Montreal, Quebec, Canada
  1. Correspondence to Dr David Watkins, 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{at}


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.

Conclusion 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.

  • Folate
  • severe combined immunodeficiency
  • megaloblastic anaemia
  • homocysteine
  • exome sequencing
  • one carbon metabolism
  • metabolic disorders
  • immunology (including allergy)
  • folate metabolism
  • genetics
  • metabolic disorders

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  • Funding This work was partially supported by grants from the Canadian Institutes of Health Research (DSR) and a Canada Research Chair (JM) and by funding from the Genetics Axis of the MUHC Research Institute and from the Lady Davis Research Institute, Jewish General Hospital.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Mcgill University Health Centre Research Ethics Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.