SHMT2 was first reported in relation to autosomal recessive neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) in 2020 (García-Cazorla, et al., 2020, PMID:33015733). Patient fibroblasts with NEDCASB were found to have altered mitochondrial membrane potentials and ROS levels. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 8 variants (missense and single amino acid deletion) have been reported in 5 probands from 2 publication (PMID:33015733, PMID:35398349). Variants in this gene segregated with disease in 1 additional family member.
The gene SHMT2 encodes an enzyme that serves as the mitochondrial form of serine hydroxymethyltransferase. Specifically, the enzyme catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate within the mitochondria. This gene-disease association is further supported by its biochemical function in kinetic assays (PMID:30500180) and a knockdown drosophila model (PMID:33015733) and a knockout mouse model (PMID:29323231), which recapitulates the molecular phenotype of deficiencies in mitochondrial respiratoration but for which homozygous knock outs are embryonic lethal at day 13.5 post coitum. The gene-disease relationship is also supported by functional alteration and rescue in cell culture models (PMIDs:29452640, 29364879), which show that null SHMT2 cells show a deficiency in respiratory chain translation due to an inability to maintain formylmethionyl-tRNA pools.
In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
This gene-disease pair was originally evaluated by the Aminoacidopathy GCEP on 11/11/2022, it was updated 07/02/2024 to reasses the NM_005412.6:c.1124-4_1125delinsA variant.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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