Inborn errors of metabolismGene: SHMT2
Comment on list classification: New gene added as Amber but can be promoted to Green at the next GMS panel update (added 'for-review' tag)
Created: 21 Dec 2020, 12:16 p.m. | Last Modified: 21 Dec 2020, 12:16 p.m.
Panel Version: 2.38
SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Created: 21 Dec 2020, 12:15 p.m. | Last Modified: 21 Dec 2020, 12:15 p.m.
Panel Version: 2.37
PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.
Clinical features include dysmorphism, congenital microcephaly, hypertrophic cardiomyopathy or atrial-septal defects, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy.
SHMT2 encodes the mitochondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.
While plasma metabolites were within normal range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts, decrease in glycine/serine ratios, impaired folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.
Created: 21 Dec 2020, 12:15 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Gene: shmt2 has been classified as Red List (Low Evidence).
gene: SHMT2 was added gene: SHMT2 was added to Inborn errors of metabolism. Sources: Literature for-review tags were added to gene: SHMT2. Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHMT2 were set to 33015733 Phenotypes for gene: SHMT2 were set to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121 Review for gene: SHMT2 was set to GREEN