Fig. 1: De novo frameshifts in HMGB1 cause BPTAS.

a, Photographs of individuals diagnosed with BPTAS. Top row, hands of I1, I2 and I5. Note brachydactyly, irregular finger length and hypoplasia of the nails. Bottom row, lower extremities of I1, I2 and I5, presenting with malformed legs, joint contractures, preaxial polysyndactyly and hypoplasia of the nails. b, Radiograms of I1, I2, I4 and I5. Top far left, limb radiograms (at newborn age) of I1 showing brachydactyly and brachyphalangy, tibial aplasia, hypoplastic fibulae and preaxial polysyndactyly. Top middle left, babygram of I2. Note tibial aplasia, hypoplastic and absent fibulae, hypoplastic pelvic bones and hypoplastic right femur. Top middle right, lower extremities of I4 (at 6 months) showing asymmetric shortness of tibiae and fibulae. Top far right, fetogram of I5 showing tibial aplasia, hypoplastic and absent fibulae, hypoplastic pelvic bones and contractures of joints. Bottom row, hand radiograms of I1, I2 (both at newborn age), I4 (at 6 months) and of I5 (at 21 weeks of gestation). Note the short middle phalanges and short proximal phalanges of the thumbs. c, Pathogenic frameshift variants in the acidic tail of HMGB1 in the individuals with BPTAS reported in this article are highlighted in red. Previously reported variants associated with developmental delay are in black. Note the genotype–phenotype correlation: C-terminal frameshifts result in BPTAS, whereas other variants lead to a neurodevelopmental phenotype. d, Amino acid sequence of the C terminus of HMGB1 in individuals with BPTAS and in selected vertebrates. Acidic residues glutamate and aspartate are shaded in red, basic residues arginine and lysine are shaded in blue. Note the replacement of the conserved acidic tail in individuals with BPTAS. e, Family pedigrees. Individuals with BPTAS are highlighted with black boxes, and the genotypes are below the boxes. f, Charge plots of WT and mutant HMGB1. I, individual; L, left; NT, not tested; R, right; WT, wild type.