AARS1

Inheritance Pattern: AR

Disease ID:MONDO:0030517

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014593

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0013212

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:1010132

Submitter: ClinGen

AARS1 was first reported in relation to an autosomal dominant form of leukoencephalopathy in 2019 in a single large Swedish family (Sundal et al., PMID: 31775912). The family was originally described in a 1984 publication as hereditary diffuse leukoencephalopathy with spheroids (Axelsson et al, PMID: 6595937) with follow-up described in a 2012 publication (Sundal et al, PMID: 22098561). Affected family members experienced variable onset (8–60 years, median: 36) of frontal lobe symptoms that progressed to encephalopathy with pyramidal, extrapyramidal, and optic tract involvement, along with ataxia, gait issues, dystonia, and vision loss; median survival was <10 years. Postmortem findings included white matter liquefaction, gliosis, axonal spheroids, and myelin loss. There were 10 clinically affected individuals in the family, two of whom underwent exome sequencing that identified a heterozygous missense variant, c.455G > T p.(Cys152Phe) in AARS1 (Sundal et al., PMID: 31775912). An additional 3 affected individuals were obligate heterozygotes, and the remaining 7 were not tested. Twenty-one unaffected relatives were tested for segregation purposes, none of whom were found to harbor the variant. No additional (unrelated) cases have been reported. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability from other disease entities associated with AARS1 variants. Therefore, the following disease entities were split and curated separately: autosomal recessive AARS1-related leukoencephalopathy (Definitive) and autosomal dominant Charcot-Marie Tooth type 2N (Definitive). A single missense variant has been reported in 2 related individuals in 1 publication in association with autosomal dominant AARS1-related leukoencephalopathy (PMID: 31775912). Functional data was available but did not provide additional information regarding variant pathogenicity. The mechanism of pathogenicity is unknown. Experimental evidence supporting or refuting the gene-disease association was not identified. In summary, there is limited evidence supporting the relationship between AARS1 and autosomal dominant AARS1-related leukoencephalopathy. This classification was approved by the Leukodystrophy and Leukoencephalopathy Working Group GCEP on March 19, 2025 [SOP Version 11].

Inheritance Pattern: AR

Disease ID:MONDO:0018614

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0030634

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0013212

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014593

Submitter: ClinGen

AARS1 was first reported in relation to autosomal recessive developmental and epileptic encephalopathy 29 (DEE29) in 2015 (OMIM: 616339, PMID: 25817015) and later in association with autosomal recessive trichothiodystrophy 8, non-photosensitive (TTD8) in 2021 (OMIM: 619691, PMID: 33909043). Additionally, AARS1 variants have been associated with autosomal dominant conditions, namely Charcot Marie Tooth type 2N (OMIM: 613287) and leukoencephalopathy, hereditary diffuse, with spheroids (HDLS2) (OMIM: 619661). These dominant disorders have been curated separately. AARS1 encodes a cytoplasmic aminoacyl-tRNA synthetase and plays a key role in the first step of protein translation through the charging of tRNA molecules with alanine (PMID: 34446925). DEE29 was initially characterized clinically as early infantile epileptic encephalopathy, deficient cerebral myelination, and peripheral neuropathy with or without congenital vertical talus (PMID: 25817015). Since that time, it has been recognized as a spectrum of infantile-onset epileptic encephalopathy with deficient myelination and late-onset disease with posterior predominant leukoencephalopathy, with the early-onset form typically presenting within the first year of life and the late-onset form presenting at variable ages >1 year (PMID: 34446925). Most affected individuals demonstrate developmental delay, seizures, truncal hypotonia, microcephaly, and develop spastic tetraparesis over time. Ophthalmologic dysfunction can also occur. Two cases of individuals presenting with autosomal recessive, nonphotosensitive trichothiodystrophy have been reported in association with bi-allelic variants in AARS1. Both patients were found to have developmental delay and neurologic regression, in addition to sulfur-deficient brittle hair and nails with ichthyosis. One patient demonstrated delayed myelination on brain MRI and both cases demonstrated impact of functional evidence of AARS1 variant on rate of tRNA charging. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability from other disease entities associated with AARS1 variants. Therefore, the following disease entities were split and curated separately: autosomal dominant AARS1-related leukoencephalopathy (Limited) and autosomal dominant Charcot-Marie Tooth type 2N (Definitive). Regarding the autosomal recessive conditions DEE29 and TTD8, we found that the phenotypes likely represent a clinical spectrum, and that there is no difference in molecular mechanism. Therefore, the DEE29 and TTD8 disease entities have been lumped into one disease entity, autosomal recessive AARS1-related leukoencephalopathy. This curation includes 20 unique variants that have been reported in the biallelic state in 16 probands across 5 publications (PMIDs: 25817015, 34446925, 33909043, 28493438, 33294374). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by a naturally-occurring mouse model as well as a yeast model. Similar to humans, the mouse model presents with ataxia and follicular dystrophy and is predicted to affect tRNA charging (PMID: 16906134). The yeast complementation model demonstrated viability through introduction of a wild-type ALA1 (yeast ortholog of AARS1) vector in haploid yeast strain with endogenous ALA deleted (PMID: 25817015). In summary, there is definitive evidence supporting the relationship between AARS1 and the disease entity now known as AARS1-related leukoencephalopathy (MONDO:0014593). 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 Leukodystrophy and Leukoencephalopathy Working Group GCEP on September 3, 2025 [SOP Version 11].

Inheritance Pattern: AR

Disease ID:MONDO:0030517

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013212

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0013212

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014593

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0030517

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014593

Submitter: PanelApp Australia