{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T06:07:17Z","timestamp":1780553237441,"version":"3.54.1"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM118647"],"award-info":[{"award-number":["GM118647"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS113515"],"award-info":[{"award-number":["NS113515"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of <jats:italic>SMN1<\/jats:italic>. However, there have been reports of SMA\u2010like disorders that are independent of <jats:italic>SMN1<\/jats:italic>, including those due to pathogenic variants in the glycyl\u2010tRNA synthetase gene (<jats:italic>GARS1<\/jats:italic>)<jats:italic>.<\/jats:italic> We report three unrelated patients with <jats:italic>de novo<\/jats:italic> variants in <jats:italic>GARS1<\/jats:italic> that are associated with infantile\u2010onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease\u2010associated <jats:italic>GARS1<\/jats:italic> variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and\/or gene panel and <jats:italic>SMN1<\/jats:italic> copy number analysis of three patients identified two previously undescribed <jats:italic>de novo<\/jats:italic> missense variants in <jats:italic>GARS1<\/jats:italic> and excluded <jats:italic>SMN1<\/jats:italic> as the causative gene. Functional studies in yeast revealed that one of the <jats:italic>de novo<\/jats:italic> <jats:italic>GARS1<\/jats:italic> variants results in a loss\u2010of\u2010function effect, consistent with other pathogenic <jats:italic>GARS1<\/jats:italic> alleles. In sum, the patients' clinical presentation, assessments of previously identified <jats:italic>GARS1<\/jats:italic> variants and functional assays in yeast suggest that the <jats:italic>GARS1<\/jats:italic> variants described here cause iSMA. <jats:italic>GARS1<\/jats:italic> variants have been previously associated with Charcot\u2013Marie\u2013Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of <jats:italic>GARS<\/jats:italic>\u2010associated disease and support that severe early\u2010onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by <jats:italic>SMN1<\/jats:italic> variants from that due to pathogenic variants in other genes such as <jats:italic>GARS1<\/jats:italic> significantly alters approaches to treatment.<\/jats:p>","DOI":"10.1002\/ajmg.a.61544","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T10:42:12Z","timestamp":1584441732000},"page":"1167-1176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["GARS\u2010related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment"],"prefix":"10.1002","volume":"182","author":[{"given":"Rebecca","family":"Markovitz","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston 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