Furthermore, our results justify revisiting the clinical phenotype of the heterozygous parent in the affected pedigrees (Simons et al., 2015) and suggest that AARS1-associated phenotypes exist along a spectrum whereby peripheral neuropathy is caused by loss-of-function, dominant-negative alleles that decrease AARS1 function with downstream effects on the integrated stress response (Spaulding et al., 2021), and that a multi-system syndrome is caused by two alleles with loss-of-function effects causing further reduction in AARS1 function. Here, AARS1 is linked to peripheral neuropathy.