Submission Details

AIMP2 was first reported in relation to neurological disease in 2016 (Helbig et al. 2016) and specifically related to autosomal recessive hypomyelinating leukodystrophy 17 (OMIM:600859) in 2018 (Shukla et al. 2018, PMID: 29215095). AIMP2 protein function is a non-enzymatic factor that is required for the assembly and stability of the aminoacyl-tRNA synthetase complex (NCBI). This disease is clinically characterized by severe infantile onset neurodevelopmental disorders with seizures, microcephaly, and white matter abnormality on MRI and additional variable findings including global developmental delay, intellectual disability, contractures, spasticity, feeding difficulties, and facial dysmorphisms (PMIDs: 26795593, 29215095, 35568357, 35140751, 38374194).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern, and therefore the single disease entity of HLD17 has been maintained. The mechanism of pathogenicity is loss of function. Six variants (2 frameshift, 2 nonsense, 1 missense, 1 splice-site) that have been reported in 7 probands in 5 publications (PMIDs: 26795593, 29215095, 35568357, 35140751, 38374194) are included in this curation. Of note, one variant (c.105C>A; Tyr35*) was observed in three probands of Indian descent and is likely a founder variant in this population.

This gene-disease relationship is also supported by protein interaction and biochemical function experiments (Kim et al., PMID: 12060739). In immunoprecipitation studies, Kim et al. showed that Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 2 (called p38 in their publication) binds to QARS1, which has been definitively associated with recessive hypomyelinating leukodystrophy 3 by the Leukodystrophy and Leukoencephalopathy GCEP. Additionally, Kim et al. showed the protein encoded AIMP2 also associated with the protein encoded by the AIMP1 gene in the multi-ARS complex, which has a definitive curation for hypomyelinating leukodystrophy 3 (PMID: 12060739). In addition, Ochiai et al 2022 demonstrated that mouse brain oligodendroglial cells with an AIMP2 homozygous variant failed to differentiate appropriately to form oligodendroglial processes required to form myelin, and therefore exhibit a process similar to hypomyelination seen in humans. In summary, there is definitive evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Leukodystrophy GCEP on the meeting date June 11, 2025 (SOP Version 11).