{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T12:23:08Z","timestamp":1771935788832,"version":"3.50.1"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Perrault syndrome (PS) is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and primary ovarian insufficiency in females.\n                      <jats:italic>LARS2<\/jats:italic>\n                      , encoding mitochondrial leucyl-tRNA synthetase, is the most common causative gene for PS. However, the genetic spectrum and clinical variability of PS remain underexplored. Expanding the catalog of\n                      <jats:italic>LARS2<\/jats:italic>\n                      variants and correlating them with phenotypic data are critical for delineating genotype-phenotype relationships.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Two unrelated Chinese probands with hearing loss were enrolled, and comprehensive clinical evaluations were performed. Whole-exome sequencing (WES) was used to identify genetic variants, followed by Sanger sequencing for family co-segregation verification. Minigene assays and RT-PCR were conducted to assess the splicing effect of the novel canonical splice-site variant\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.235-2A&amp;gt;G. For the novel missense variant\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.1661T&amp;gt;C, 3-D structural modeling and evolutionary conservation analysis were performed to evaluate its pathogenicity. Moreover, we comprehensively summarized all\n                      <jats:italic>LARS2<\/jats:italic>\n                      variants associated with PS via an extensive literature review.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Proband 1 (12-year-old female) harbors compound heterozygous variants\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.235-2A&amp;gt;G (novel) and\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.880G&amp;gt;A, presenting with profound SNHL, primary ovarian insufficiency, and developmental delay. Proband 2 (7-year-old male) carries compound heterozygous variants\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.1661T&amp;gt;C (novel) and\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.1886C&amp;gt;T, manifesting severe SNHL with an unusual upsloping audiogram pattern and comprehension difficulties. Functional assays confirmed that\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.235-2A&amp;gt;G disrupts canonical splicing, leading to exon 4 skipping and in-frame deletions. 3-D structural modeling and conservation analysis revealed that\n                      <jats:italic>LARS2<\/jats:italic>\n                      c.1661T&amp;gt;C likely impairs protein stability by altering residue interactions, with Val554 being highly conserved across species. According to the ACMG\/AMP guideline, both novel LARS2 variants were classified as likely pathogenic.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We identified two novel\n                      <jats:italic>LARS2<\/jats:italic>\n                      variants associated with PS in Chinese patients, thereby expanding the\n                      <jats:italic>LARS2<\/jats:italic>\n                      genetic spectrum and providing precise molecular evidence for clinical management and genetic counseling. This study enhances understanding of genotype-phenotype correlations in PS, thereby revealing the phenotypic heterogeneity of\n                      <jats:italic>LARS2<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1785502","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T22:10:12Z","timestamp":1771366212000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel LARS2 variants in patients with Perrault syndrome: expanding the genetic spectrum and phenotypic heterogeneity"],"prefix":"10.3389","volume":"17","author":[{"given":"Zibin","family":"Lin","sequence":"first","affiliation":[{"name":"Reproductive Medicine Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University","place":["Guangzhou, Guangdong, China"]},{"name":"College of Life Sciences, University of 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