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Diagnosing CCLA is challenging due to its broad spectrum of symptoms, including nonimmune fetal hydrops, chylothorax, chylous ascites, or lymphedema. For that reason, genetic diagnosis is essential to uncover new genes and variants causing this debilitating disease. A patient with complex congenital heart disease presented with post\u2010operative refractory chylothorax. Lymphatic imaging demonstrated abnormal intercostal lymphatic perfusion consistent with CCLA and suggestive of a RASopathy, a group of genetic disorders characterized by dysregulated RAS\u2010MAPK signaling. Genetic testing showed a variant of uncertain significance (p.(Ala308Val)) in\n                    <jats:italic>SHOC2,<\/jats:italic>\n                    a scaffolding protein that regulates RAS\u2010MAPK signaling but has not yet been described in CCLA. Trametinib, a MEK1\/2 inhibitor, was trialed without improvement. A conversion\/extension assay was used to evaluate pathogenicity of the VUS compared to a known pathogenic variant. Zebrafish transiently expressing the wild type human SHOC2 protein or SHOC2 p.(Ala308Val) protein in the developing lymphatic and venous endothelium were used to evaluate the effect on the vasculature. Western blot was used to explore the underlying molecular mechanisms. Major to minor axis ratio was significantly increased in developing embryos injected with\n                    <jats:italic>SHOC2<\/jats:italic>\n                    r.923c&gt;u mRNA, indicating pathogenicity through dysregulation of MAPK\/mTOR signaling. Zebrafish transiently expressing SHOC2 p.(Ala308Val) in the lymphovenous endothelium developed pericardial edema and cystic malformations of the caudal plexus and dilation of the thoracic duct. In concordance with the lack of clinical response to trametinib, immunoblot results indicate that SHOC2 p.(Ala308Val) may be inducing lymphatic malformations through non\u2010canonical mTOR signaling rather than dysregulated RAS\u2010MAPK signaling.\n                    <jats:italic>SHOC2<\/jats:italic>\n                    is a novel cause of central conducting lymphatic anomaly. Future research should investigate the cellular and molecular mechanisms as well as therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70224","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T08:58:36Z","timestamp":1784105916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>\n                      <i>SHOC2<\/i>\n                    <\/scp>\n                    Is a Novel Cause of Central Conducting Lymphatic Anomaly"],"prefix":"10.1002","author":[{"given":"Jessica C.","family":"Ding","sequence":"first","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Sempowski","sequence":"additional","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lola","family":"Zerbib","sequence":"additional","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4313-0983","authenticated-orcid":false,"given":"Gregory T.","family":"Adamson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Cardiology Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Insinna","sequence":"additional","affiliation":[{"name":"Aquaculture Core, Laboratory of Cell and Developmental Signaling, National Cancer Institute  Frederick Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4737-4750","authenticated-orcid":false,"given":"Sanjay P.","family":"Sinha","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology University of Los Angeles Mattel Children's Hospital  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey J.","family":"Breckenridge","sequence":"additional","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel R.","family":"Amedume","sequence":"additional","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica T. E.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia L.","family":"Krikorian","sequence":"additional","affiliation":[{"name":"Unit on Vascular Malformations <i>Eunice Kennedy Shriver<\/i> National Institute for Child Health and Human Development  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Dykzeul","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University School of Medicine  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan J.","family":"Floyd","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Cardiology Stanford University School of 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