SHOC2 Is a Novel Cause of Central Conducting Lymphatic Anomaly.

SHOC2 missense variant (a RAS-MAPK scaffolding protein) acting through non-canonical mTOR signalling rather than RAS-MAPK.

In a patient with complex congenital heart disease and refractory post-operative chylothorax, lymphatic imaging suggested a RASopathy-type central conducting lymphatic anomaly (CCLA). Sequencing revealed a variant of uncertain significance (p.Ala308Val) in SHOC2, a RAS-MAPK scaffolding protein not previously described in CCLA. Trametinib (a MEK1/2 inhibitor) was trialled without improvement. Functional assays (conversion/extension assay, zebrafish expressing the variant in lymphovenous endothelium, western blot) confirmed pathogenicity through non-canonical mTOR signalling rather than RAS-MAPK — consistent with the lack of response to trametinib.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

SHOC2 is already a known RASopathy gene; the contribution here is phenotypic expansion to CCLA and, above all, the non-canonical (mTOR) mechanism, which explains the trametinib failure and points to other targets. A nice example where precision medicine fails for want of the right pathway, and where functional work corrects the therapeutic course. It remains a single case, to be replicated.

Analysis by Dr Thibaut Benquey