{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:02:30Z","timestamp":1790071350833,"version":"4.0.1"},"reference-count":5,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM136441"],"award-info":[{"award-number":["GM136441"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Peripheral Nervous Sys"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>HARS1<\/jats:italic>\n                      gene encodes cytoplasmic histidyl\u2010tRNA synthetase, which catalyzes the ligation of histidine to tRNA\n                      <jats:sup>HIS<\/jats:sup>\n                      in the cytoplasm as an early step in protein biosynthesis and is essential for cell viability. Pathogenic variants in\n                      <jats:italic>HARS1<\/jats:italic>\n                      have been associated with three phenotypes: autosomal dominant Charcot\u2013Marie\u2013Tooth (CMT) disease, a multisystem recessive syndrome with prominent ataxia, and autosomal recessive Usher syndrome. Here, we present a patient who is compound heterozygous for\n                      <jats:italic>HARS1<\/jats:italic>\n                      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\n                      <jats:italic>HARS1<\/jats:italic>\n                      \u2010related disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The individual found to have pathogenic compound heterozygous\n                      <jats:italic>HARS1<\/jats:italic>\n                      variants was evaluated in a neuromuscular clinic and was further investigated in research studies. Functional consequences of the\n                      <jats:italic>HARS1<\/jats:italic>\n                      variants were tested in yeast complementation assays; the phase of these alleles was confirmed via long\u2010range PCR and long\u2010read sequencing on DNA isolated from the proband, the mother, and the father.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A 25\u2010year\u2010old male with CMT1 and mild intellectual disability had a maternally inherited variant (p.Q410*) and a de novo variant in the\n                      <jats:italic>HARS1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Studies in yeast revealed loss\u2010of\u2010function characteristics for both p.Q410* and p.R375C\n                      <jats:italic>HARS1<\/jats:italic>\n                      , consistent with these variants being pathogenic. Allele\u2010specific 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\n                      <jats:italic>HARS1<\/jats:italic>\n                      variants are responsible for the recessive phenotype. This case report expands the allelic and phenotypic heterogeneity of biallelic\n                      <jats:italic>HARS1<\/jats:italic>\n                      pathogenic variants.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jns.70162","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T14:10:02Z","timestamp":1786630202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuropathy With Demyelinating Features in a Patient With Biallelic\n                    <scp>\n                      <i>HARS1<\/i>\n                    <\/scp>\n                    Variants"],"prefix":"10.1111","volume":"31","author":[{"given":"Christina","family":"Del Greco","sequence":"first","affiliation":[{"name":"Department of Human Genetics University of Michigan Medical School  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison R.","family":"Cale","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of Michigan Medical School  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5913-0015","authenticated-orcid":false,"given":"Karl","family":"Haeberlein","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of Michigan Medical School  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-3156","authenticated-orcid":false,"given":"Anthony","family":"Antonellis","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of Michigan Medical School  Ann Arbor Michigan USA"},{"name":"Department of Neurology University of Michigan Medical School  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-6971","authenticated-orcid":false,"given":"Michael E.","family":"Shy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2236-9218","authenticated-orcid":false,"given":"Tiffany","family":"Grider","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx231"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028936"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24024"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22210"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010019\u20100690\u20102"}],"container-title":["Journal of the Peripheral Nervous System"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jns.70162","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jns.70162","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jns.70162","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:14:58Z","timestamp":1790068498000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jns.70162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":5,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/jns.70162"],"URL":"https:\/\/doi.org\/10.1111\/jns.70162","archive":["Portico"],"relation":{},"ISSN":["1085-9489","1529-8027"],"issn-type":[{"value":"1085-9489","type":"print"},{"value":"1529-8027","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]},"assertion":[{"value":"2026-07-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70162"}}