MTHFD1

Inheritance Pattern: AR

Disease ID:MONDO:0060611

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0060611

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0060611

Submitter: ClinGen

*MTHFD1* was first reported in relation to autosomal recessive combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia in 2011 (Watkins et al., PMID: 21813566). Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (CIMAH) is an inborn error of folate metabolism due to deficiency of methylenetetrahydrofolate dehydrogenase-1. Manifestations may include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mildly impaired intellectual development, lymphopenia involving all subsets, and low T-cell receptor excision circles. Seven variants (including missense and nonsense) that have been reported in four probands in four publications (PMIDs: 32414565, 23296427, 25633902, 21813566) are included in this curation. The mechanism of pathogenicity appears to be partial loss of function. This gene-disease relationship is also supported by experimental evidence (e.g. animal models, expression studies, biochemical function, functional alteration) (PMIDs: 32414565, 25633902, 19033438). Experimental evidence from an animal model study using mice demonstrates that the *MTHFD1* gene is essential in mice as all *MTHFD1*-null mice were shown to be not viable in the study (MacFarlane et al., PMID: 19033438). Skin fibroblasts taken from patients with biallelic *MTHFD1* variants were shown to have decreased Mthfd1 protein activity compared to heterozygote relatives as well as controls (Bidla et al., PMID: 32414565). While heterozygous carriers present with no clinical symptoms of *MTHFD1* deficiency, in vitro enzyme testing suggests that heterozygous carriers have enzyme activity levels that are approximately half that of non-carriers. In summary, there is definitive evidence supporting the relationship between the *MTHFD1* gene and autosomal recessive combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date April 16, 2026 (SOP Version 12).