SHOC2 Is a Novel Cause of Central Conducting Lymphatic Anomaly

Central conducting lymphatic anomaly (CCLA) is a devastating disorder where precision medicine can be lifesaving. 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-operative 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-MAPK signaling. Genetic testing showed a variant of uncertain significance (p.(Ala308Val)) in SHOC2, a scaffolding protein that regulates RAS-MAPK 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 SHOC2 r.923c>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-canonical mTOR signaling rather than dysregulated RAS-MAPK signaling. SHOC2 is a novel cause of central conducting lymphatic anomaly. Future research should investigate the cellular and molecular mechanisms as well as therapeutics.