Fig. 1: SETBP1 variants outside the degron cluster in the SKI domain, facial photographs and speech phenotyping of individuals with SETBP1 variants.
a Schematic representation of the SETBP1 protein (UniProt: Q9Y6X0) indicating the locations of variants included in this study. These comprise eleven novel germline variants (circles), including ten missense variants (blue) and one in-frame deletion (de novo, green) outside the canonical degron. Three missense variants outside (blue) and nine within (orange) the degron that were previously reported (diamond) are also annotated in the schematic. § represent variants for which speech phenotyping data were available. # represent variants included in functional assays. Five exons (black bars) encode isoform A of the protein (NP_056374.2, 1596 amino acids). The known SETBP1 protein domains are indicated7,21,22. An overview with variant details per subject is provided in Supplementary Data 1. b For individuals with an amino acid change in the 854–858 region, no visually recognisable facial features could be delineated. Shared facial features present in at least three out of five individuals with an amino acid change in 862–874 include prominent ears, shallow orbits, midface retraction, and microcephaly. Individuals with a 962 and 957 variant show similar facial features, including a round face, blepharophimosis, ptosis, hypertelorism, and a short nose with a bulbous tip, features that are also often noted in individuals with SETBP1 haploinsufficiency disorder. c PhenoScore is able to distinguish individuals with SGS and SETBP1-haploinsufficiency disorder. Subgroup analysis of (left) facial photographs and (right) phenotypic data (HPO terms) of five individuals with SGS and five individuals with SETBP1-haploinsufficiency disorder. Score: 0 = SETBP1-haploinsufficiency disorder; 1 = SGS. d Phenotypic similarity of individuals with missense SETBP1 variants outside the degron predicted using PhenoScore (purple circle), HPO terms only (green) or facial features only (blue). Score: 0 = SETBP1-haploinsufficiency disorder; 1 = SGS. Each datapoint represents one individual (n = 18). Details in Supplementary Data 2. e Performance on Vineland-3 subtests. Lines denote median scores; X denotes mean scores; ABC, Adaptive Behaviour Composite. Standard scores between 85 and 115 are considered within the average range, with a mean of 100 and a standard deviation of 15. The performance of five individuals was measured. All details of statistical tests and p-values are provided in Source Data 2. Source data are provided as a Source Data file.
