A recurrent de novo damaging variant in EMP2 causes progressive symmetric erythrokeratoderma

Genetic investigation in Mendelian skin disorders featuring generalized or localized skin scaling and redness, known as the ichthyoses, has revealed novel pathways relevant to epidermal integrity, barrier function, and desquamation. Here, we show that a recurrent de novo missense variant in EMP2 (epithelial membrane protein 2), which encodes a cell surface tetraspan protein in the growth-arrest specific 3 (GAS3)/peripheral myelin protein 22 (PMP22) family, is associated with a Mendelian skin disorder in the progressive symmetric erythrokeratoderma spectrum. The disorder features severely thickened, red, and scaly skin at sites of wound healing or repetitive movement including on the face, genitals, flexural areas, and the palms and soles. EMP2 has previously been shown to directly associate with focal adhesion kinase, which links cell junction forces to signaling pathways relevant to proliferation, migration, and wound healing. Using single-cell spatial transcriptomics in affected tissue, we found ectopic suprabasal activation of signaling pathways downstream of receptor tyrosine kinases including epidermal growth factor receptor (EGFR), which we confirmed with western blotting in affected cells, supporting a gain-of-function mechanism for mutant EMP2. Remarkably, treatment with erlotinib, an EGFR inhibitor, led to marked clinical improvement underscoring the key role of EMP2 in epidermal differentiation and proliferation.