Schematic representation of LRP2 mutations and corresponding megalin domains. LRP2 sequencing uncovered missense, nonsense, frameshift or splice junction mutations in individuals with DBS/FOAR from seven kindreds. Mutations are indicated adjacent to the megalin extracellular domains that they affect; mutation ‘hotspots’ or genotype-phenotype correlations are not apparent. Mat, maternally inherited mutation; pat, paternally inherited mutation (Supplementary Table 3).

MRI abnormalities in individuals with DBS/FOAR. (a) Sagittal T1-weighted magnetic resonance image of subject 1, kindred 5, showing ACC with associated absence of cingulate gyrus. (b) Sagittal T1-weighted magnetic resonance image of subject IV-6, kindred 1, showing arrested development of corpus callosum with truncation of posterior body, absence of splenium and rostrum of corpus callosum, partially empty sella (s) and small-appearing pons (P). (c,d) Axial FSE T2-weighted magnetic resonance image of subject IV-6, kindred 1, showing subependymal nodular heterotopia (c) and enlarged globes with small colobomas at the optic nerve heads (d). (e) Axial computed tomography of temporal bones of subject IV-6, kindred 1, showing globular malformation of the left horizontal semicircular canal and vestibule. Abnormalities are indicated by arrows in a–e. (f–i) Brain cortical surface reconstruction from spoiled gradient-echo (SPGR) structural magnetic resonance image. f shows a frontal right view and g shows a top view for a 4-year-old control. Central sulcus, precentral gyrus and postcentral gyrus are labeled by a red curve, a white arrow and a yellow arrow, respectively. h shows a frontal right view and i shows a top view for subject IV-6, kindred 1, with DBS/FOAR. Note abnormally developed frontal lobe and unrecognizable abnormally placed central sulcus.