Analysis of the mutational status of the ligands (TGFB1-3), receptors (TGFBR1-3) and SMADs (SMAD2-4) in 1121 iCCA patients revealed a low mutation frequency in these genes, with driver mutations present in only 6.6% of patients (Fig. 1e). Here, SMAD2 is linked to infantile convulsions and choreoathetosis.