Fig. 3: Variants identified in this cohort and aminoacylation studies of affected individuals.

(a) Schematic overview of the AlaRS functional domains and variants identified within this cohort. The amino acid changes caused by previously identified variants (Lys81Thr, Tyr690Leufs*3, and Arg751Gly) are marked with an #. One individual (I-4) was found to have a structural variant (not shown). Variants associated with late-onset disease are designated with a °, variants designated with a ^ are seen in both phenotypes, and all other variants are associated with early infantile–onset disease. Variants below the domain markings and colored in gray are previously associated with autosomal dominant Charcot–Marie–Tooth disease, type 2N. (b) Aminoacylation studies performed in triplicate on fibroblast lysates from three individuals with late-onset AARS1-related disease noted with a ° and two with the more severe early infantile–onset form shown diminished AlaRS activity relative to a control sample and using ArgRS activity as an in-sample control. Activity is more severely reduced in three individuals, including two (I-7 and I-9) with early infantile–onset disease and one individual (I-4) with later disease onset but a rapidly progressive course. Bars represent average ± standard deviation.