Kesava A Ramakrishnan, Reuben J Pengelly, Yifang Gao, Mary Morgan, Sanjay V Patel, E Graham Davies, Sarah Ennis, Saul N Faust, Anthony P Williams
Journal: The journal of allergy and clinical immunology. In practice 2017;4(6):1160-1166.e10
PMID: 27707659
BACKGROUND
Methylenetetrahydrofolate dehydrogenase (MTHFD1) deficiency has recently been reported to cause a folate-responsive syndrome displaying a phenotype that includes megaloblastic anemia and severe combined immunodeficiency.
OBJECTIVE
To describe our investigative approach to the molecular diagnosis and evaluation of immune dysfunction in a family with MTHFD1 deficiency.
METHODS
The methods used were exome sequencing and analysis of variants in genes involved in the folate metabolic pathway in a family with 2 affected siblings. Routine laboratory and research data were analyzed to gain an in-depth understanding of innate, humoral, and cell-mediated immune function before and after folinic acid supplementation.
RESULTS
Interrogation of exome data for concordant variants between the siblings in the genes involved in folate metabolic pathway identified a heterozygous mutation in exon 3 of the MTHFD1 gene that was shared with their mother. In view of highly suggestive phenotype, we extended our bioinformatics interrogation for structural variants in the MTHFD1 gene by manual evaluation of the exome data for sequence depth coverage of all the exons. A deletion involving exon 13 that was shared with their father was identified. Routine laboratory data showed lymphopenia involving all subsets and poor response to vaccines. In vitro analysis of dendritic cell and lymphocyte function was comparable to that in healthy volunteers. Treatment with folinic acid led to immune reconstitution, enabling discontinuation of all prophylactic therapies.
CONCLUSIONS
Exome sequencing demonstrated MTHFD1 deficiency as a novel cause of a combined immunodeficiency. Folinic acid was established as precision therapy to reverse the clinical and laboratory phenotype of this primary immunodeficiency.
Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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