Neuropathy With Demyelinating Features in a Patient With Biallelic HARS1 Variants
ABSTRACT Background and Aims The HARS1 gene encodes cytoplasmic histidyl‐tRNA synthetase, which catalyzes the ligation of histidine to tRNAHIS in the cytoplasm as an early step in protein biosynthesis and is essential for cell viability. Pathogenic variants in HARS1 have been associated with three phenotypes: autosomal dominant Charcot–Marie–Tooth (CMT) disease, a multisystem recessive syndrome with prominent ataxia, and autosomal recessive Usher syndrome. Here, we present a patient who is compound heterozygous for HARS1 variants and who has a complex recessive phenotype that includes a neuropathy with demyelinating features and active denervation. Our computational and functional analyses support the pathogenicity of these alleles, suggesting that our findings expand the allelic and clinical heterogeneity of HARS1‐related disease. Methods The individual found to have pathogenic compound heterozygous HARS1 variants was evaluated in a neuromuscular clinic and was further investigated in research studies. Functional consequences of the HARS1 variants were tested in yeast complementation assays; the phase of these alleles was confirmed via long‐range PCR and long‐read sequencing on DNA isolated from the proband, the mother, and the father. Results A 25‐year‐old male with CMT1 and mild intellectual disability had a maternally inherited variant (p.Q410*) and a de novo variant in the HARS1 gene (p.R375C) identified via trio exome sequencing. Studies in yeast revealed ablated function for p.Q410* and reduced function for p.R375C. Of 2480 informative sequencing reads generated from the proband: (a) 1765 (71%) included only p.R375C or only p.Q410*; (b) 237 (10%) included both alleles; and (c) 478 (19%) included neither allele. Interpretation Studies in yeast revealed loss‐of‐function characteristics for both p.Q410* and p.R375C HARS1, consistent with these variants being pathogenic. Allele‐specific sequencing analyses are consistent with the proband having a compound heterozygous genotype and with p.R375C being a de novo variant that arose on the chromosome 5 transmitted by the father. There is therefore moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype. This case report expands the allelic and phenotypic heterogeneity of biallelic HARS1 pathogenic variants.