MAP1B mutations cause intellectual disability and extensive white matter deficit

Abstract

Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Whole-genome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (β = −2.1SD, P = 5.1 × 10−8), 47% less corpus callosum (CC) volume (β = −2.4SD, P = 5.5 × 10−10) and lower brain-wide fractional anisotropy (P = 6.7 × 10−4). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.