AIMP1 was first reported in relation to autosomal recessive hypomyelinating leukodystrophy 3 (HLD3) (OMIM:603605) in 2010 (Feinstein et al., PMID: 21092922). AIMP1 protein function is important in joining tRNAs to their cognate amino acids and in interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes (Khan et al., PMID:30828585). This disease is clinically characterized by developmental delay, microcephaly, and white matter abnormality on MRI and additional variable findings including epilepsy, hypotonia, spasticity, and cerebral atrophy (Hori et al. 2021, PMID: 33402283).
Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern. The mechanism of pathogenicity is loss of function. Seven variants (3 frameshift, 2 nonsense, 1 missense, 1 splice-site) that have been reported in 18 probands in 7 publications (PMIDs: 21092922, 24958424, 30486714, 30477741, 31618474, 36368352, 36652953) are included in this curation. Of note, one variant (c.115C > T; p.Gln39*) was observed in five probands of Filipino descent and is likely a founder variant in this population. At least two families (seven total affected individuals) with homozygous missense variants in AIMP1 were found to have an isolated neurodevelopmental phenotype (intellectual disability) without hypomyelination or neurodegeneration (PMID: 26173967). Therefore, these probands were not included in this curation, and more evidence is needed to determine if these individuals are representative of a separate disease entity or a wider phenotype spectrum of HLD3. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
This gene-disease relationship is also supported by an animal model (Zhu et al., PMID: 19717447). Zhu et al. showed that a mouse model lacking the MSC p43 protein exhibited axon degeneration in motor neurons, defective neuromuscular junctions, muscular atrophy, and motor dysfunction (PMID: 19717447). In summary, there is definitive evidence supporting the relationship between AIMP1 and hypomyelinating leukodystrophy 3 (MONDO:0009843), also known as AIMP1-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy GCEP on the meeting date December 18, 2024 (SOP Version 11).
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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