{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:10:58Z","timestamp":1781629858288,"version":"3.54.5"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Primary lymphedema (PL) is a genetically heterogeneous disorder of the lymphatic system. Despite the identification of numerous monogenic causes, the genetic etiology of many familial cases remains elusive, often exhibiting marked phenotypic variability that suggests non-Mendelian or complex inheritance patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We investigated a four-generation Chinese pedigree presenting with autosomal dominant generalized lymphedema affecting all four limbs, with marked phenotypic variability. Whole-exome sequencing in eight key family members, followed by Sanger sequencing in all 26 available relatives, identified two novel heterozygous missense variants that co-segregated with the disease:\n                      <jats:italic>GJC2<\/jats:italic>\n                      c.287G\u2009&gt;\u2009T (p.Gly96Val) and\n                      <jats:italic>OBSCN<\/jats:italic>\n                      c.22393T\u2009&gt;\u2009A (p.Phe7465Ile). The\n                      <jats:italic>GJC2<\/jats:italic>\n                      variant affects the second transmembrane domain of connexin 47, whereas the\n                      <jats:italic>OBSCN<\/jats:italic>\n                      variant lies in immunoglobulin-like domain 55 of obscurin, a large cytoskeletal signaling protein not previously implicated in lymphedema. In silico structural modeling predicted that both variants alter local packing and compromise protein stability. Haplotype analysis revealed that these two genes, located approximately 210 kb apart on chromosome 1q42.13, reside on a shared haplotype block with linkage disequilibrium, consistent with co-inheritance as a single pathogenic haplotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      To our knowledge, this is the first report linking\n                      <jats:italic>OBSCN<\/jats:italic>\n                      to human lymphedema. We propose a synergistic oligogenic model in which\n                      <jats:italic>GJC2<\/jats:italic>\n                      disruption impairs lymphatic pumping coordination, while the co-segregating\n                      <jats:italic>OBSCN<\/jats:italic>\n                      variant compromises cytoskeletal integrity and RhoA signaling in lymphatic endothelial cells; together these effects could explain the early-onset, severe phenotype observed in this family. These findings expand the genetic spectrum of PL and highlight the importance of considering closely linked modifier genes in complex inheritance patterns.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04196-7","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T16:55:36Z","timestamp":1768323336000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel GJC2 and OBSCN variants co-segregating in a Chinese primary lymphedema pedigree"],"prefix":"10.1186","volume":"21","author":[{"given":"Xiaoqian","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang","family":"Ju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runlin Z.","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuguang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5598-6039","authenticated-orcid":false,"given":"Jiawei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"issue":"6","key":"4196_CR1","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.ajhg.2010.04.010","volume":"86","author":"RE Ferrell","year":"2010","unstructured":"Ferrell RE, Baty CJ, Kimak MA, Karlsson JM, Lawrence EC, Frankesnyder M, et al. 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Written informed consent for the research use of samples and participation was obtained from all subjects; for individuals under the age of 18, written consent was provided by their parents or legal guardians. All methods were carried out in accordance with relevant guidelines and regulations, including the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from all patients (or their legal guardians) for the publication of any potentially identifiable information or images included in this article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17"}}