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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 (SCID). Objective: To describe our investigative approach to the molecular diagnosis and evaluation of immune dysfunction in a family with MTHFD1 deficiency. Methods: Exome sequencing and analysis of variants in genes involved in the folate metabolic pathway in a family with two 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 were comparable to healthy volunteers. We will email all CoI forms as soon as we have them from all authors but have not delayed this resubmission. Responses to Comments