a, Schematic representation of functional domains of βII-spectrin. CH1, calponin homology domain 1 (teal); CH2, calponin homology domain 2 (red); SR, spectrin repeat (green); PH, pleckstrin homology domain (purple). The locations of SPTBN1 variants are indicated. b, Alignment of protein sequences for βII-spectrin and orthologs show that missense variants identified in affected individuals in this study are located at highly conserved residues across species from humans to Drosophila. Accession numbers: human (Homo Sapiens, NP_003119.2), chimp (Pan troglodytes, XP_001154155.1), mouse (Mus musculus, NP_787030.2), frog (Xenopus tropicalis, NP_001362280.1), zebrafish (Danio rerio, XP_009304586.2), worm (C. elegans, NP_001024053.2), fly (Drosophila melanogaster, NP_001259660.1). The position of SPTBN1 variants analyzed in the sequenced of human βII-spectrin is shown for reference. c, Photos of individuals with SPTBN1 variants. Ages at the time of photograph are: P8, 7y8m; P9, 16y; P12, 11y; P13, 6y; P21 left, unknown; P21 right, 11y; P22, 15y; P28, 3y11m. d, Examples of brain MRI findings: diffuse cerebral parenchymal volume loss (L>R) and asymmetric appearance of hippocampi (P1, acquired at <1y), white matter disease in the supratentorial and infratentorial regions (P18, acquired at 7y), thinning of the posterior body of the corpus callosum without significant volume loss (P28, acquired at 10m).