Likely inborn error of metabolism

Gene: SHMT2

The rating of this gene has been updated following NHS Genomic Medicine Service approval

Created: 3 Mar 2022, 12:59 p.m. | Last Modified: 3 Mar 2022, 12:59 p.m.

Panel Version: 2.223

Green List (high evidence)

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.
Sources: Literature

Created: 21 Dec 2020, 12:15 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121

Publications

• 33015733