Submission Details

AARS1 was first reported in relation to autosomal dominant Charcot-Marie-Tooth disease type 2N in 2010 (Latour et al., PMID:20045102). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern AND/OR phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, Charcot-Marie-Tooth, axonal, type 2N (OMIM:613287), Developmental and epileptic encephalopathy 29 (OMIM: 616339), and Trichothiodystrophy 8, nonphotosensitive (OMIM: 619691). Age of onset for CMT2N ranges from adolescence to early adulthood and the phenotype consists of reduced or absent tendon reflexes, distal motor weakness, and often sensory disturbances. Electromyographic studies demonstrate sensory and motor axonal neuropathy. Five missense variants that have been reported in seven probands in four publications (PMIDs: 20045102, 22009580, 22206013, 30124830) are included in this curation. The mechanism of pathogenicity appears to be gain of function. This gene-disease relationship is also supported by aminoacylation assays, rescue experiments in yeast, and a zebrafish model (PMIDs: 22009580, 33753480, 30124830). McLaughlin et al., 2012 demonstrated a reduction in AARS enzyme activity by measuring aminoacylation of tRNA(Ala) by WT, N71Y, and R329H AARS enzymes. Additionally, ALA1 null Saccharomyces cerevisiae were transfected with WT, N71Y, or R329H ALA1, or an empty vector and yeast viability measured. N71Y and R329H ALA1 were unable to rescue the ALA1 null yeast. This experiment was repeated by Waterman et al., 2018 for three more variants, showing that the R326W and S627L variants are also unable to rescue ALA1 null yeast, while the E337K variant increased growth when compared to WT ALA1. Waterman et al., used a morpholino zebrafish model to further investigate the R326W, S627L, and E337K mutations. Injections of mutant mRNA produced toxicity in Zebrafish embryos and showed an irregular and less well defined pattern of nerves across each somite, which equal injections of WT mRNA did not produce. In summary, there is definitive evidence supporting the relationship between AARS1 and autosomal dominant Charcot-Marie-Tooth disease axonal type 2N. 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 Charcot-Marie-Tooth disease GCEP on the meeting date September 12, 2023 (SOP Version 9).