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Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by  de novo  germline mutations clustering to a 12bp hotspot in exon 4 of  SETBP1 . Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping  SETBP1  hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline  SETBP1  mutations and of four individuals with a milder phenotype caused by  de novo  germline mutations adjacent to the  SETBP1  hotspot. Different mutations within and around the  SETBP1  hotspot have varying effects on SETBP1 stability and protein levels  in vitro  and in  in silico  modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation  in vitro  and higher incidence of cancer compared to patients with other germline  SETBP1  mutations. Our findings substantiate that, despite their overlap, somatic  SETBP1  mutations driving malignancy are more disruptive to the degron than germline  SETBP1  mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic  SETBP1  mutations in leukemia, our results reveal a genotype-phenotype correlation in germline  SETBP1  mutations spanning a molecular, cellular and clinical phenotype.

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies