Figure 1.

Clinical presentation and HEATR3 variants that drive DBA. (A) Photographs of the face and hands of the affected P1, P2, P3, P5, and P6 (photos from Family C not available). No common facial finding was present in affected individuals, but straight eyebrows, down-slanting palpebral fissures, and synophrys are apparent in some. Note that fingers in P1, P3, and P6 appear disproportionately short compared with the hand. Also note the presence of thumb anomaly in P5. (B) The pedigrees of Families A to D with genotypes for specified HEATR3 variants are indicated below each available individual. The pathogenic variants are indicated in red. (C) HEATR3 variants cosegregating with DBA in one affected individual from each family arranged according to position of coding sequence in ascending order. The missense variants c.400T>C (p.Cys134Arg) in P5, c.1337G>A (p.Cys446Tyr) in P3, and c.1751G>A (p.Gly584Glu) in P1 and P2 are homozygous; the splice donor site variant c.399 + 1G>T (p.?) and the missense variant c.719C>T (p.Pro240Leu) are compound heterozygous in P4. (D) Schematic representation of HEATR3 with 15 exons. (E) HEATR3 protein with four ARM (Armadillo) and six HEAT (Huntingtin, Elongation factor 3, protein phosphatase 2A, and Target of rapamycin 1) repeat domains, indicating the position of associated variants. The protein domains have been described previously.^27,28