Submission Details

ASNS was first reported in relation to autosomal recessive asparagine synthetase deficiency in 2013 (Ruzzo et al., PMID: 24139043). Individuals with mutations in the ASNS gene exhibit developmental delays, intellectual disability, microcephaly, intractable seizures, and progressive brain atrophy. Currently, the disease requires molecular diagnosis as some, but not all, affected individuals have a measurable decrease in the amount of asparagine in their serum or cerebrospinal fluid, which limits this analysis as a preliminary screen in suspected cases. At least 24 unique variants (primarily missense but also frameshift and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 22 probands in 15 publications (PMIDs: 29375865, 25663424, 25227173, 29405484, 28776279, 30315573, 26318253, 24139043, 29279279, 30057589, 27422383, 27711071, 27469131, 27743885, 26395554). Variants in this gene segregated with disease in 10 additional family members. Molecular modeling using the Escherichia coli ASNS-B structure has revealed that most of the reported ASD substitutions are located near catalytic sites or within highly conserved regions of the protein (Reviewed in PMID: 29084849). This gene-disease association is supported by its biochemical function in asparagine synthesis, the functional alteration in patient cells resulting in decreased proliferation, the pattern of expression in the brain similar to that of known microcephaly genes, and a hypomorphic mouse model which recapitulates the human brain phenotypes. In summary, ASNS is definitively associated with autosomal recessive inheritance of asparagine synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.