MAP1B mutations cause intellectual disability and extensive white matter deficit

G. Bragi Walters, Omar Gustafsson, Gardar Sveinbjornsson, Valgerdur K. Eiriksdottir, Arna B. Agustsdottir, Gudrun A. Jonsdottir, Stacy Steinberg, Arni F. Gunnarsson, Magnus I. Magnusson, Unnur Unnsteinsdottir, Amy L. Lee, Adalbjorg Jonasdottir, Asgeir Sigurdsson, Aslaug Jonasdottir, Astros Skuladottir, Lina Jonsson, Muhammad S. Nawaz, Patrick Sulem, Mike Frigge, Andres Ingason, Askell Love, Gudmundur L. Norddhal, Mark Zervas, Daniel F. Gudbjartsson, Magnus O. Ulfarsson, Evald Saemundsen, Hreinn Stefansson () and Kari Stefansson ()
Additional contact information
G. Bragi Walters: deCODE genetics/Amgen
Omar Gustafsson: deCODE genetics/Amgen
Gardar Sveinbjornsson: deCODE genetics/Amgen
Valgerdur K. Eiriksdottir: deCODE genetics/Amgen
Arna B. Agustsdottir: deCODE genetics/Amgen
Gudrun A. Jonsdottir: deCODE genetics/Amgen
Stacy Steinberg: deCODE genetics/Amgen
Arni F. Gunnarsson: deCODE genetics/Amgen
Magnus I. Magnusson: deCODE genetics/Amgen
Unnur Unnsteinsdottir: deCODE genetics/Amgen
Amy L. Lee: deCODE genetics/Amgen
Adalbjorg Jonasdottir: deCODE genetics/Amgen
Asgeir Sigurdsson: deCODE genetics/Amgen
Aslaug Jonasdottir: deCODE genetics/Amgen
Astros Skuladottir: deCODE genetics/Amgen
Lina Jonsson: deCODE genetics/Amgen
Muhammad S. Nawaz: deCODE genetics/Amgen
Patrick Sulem: deCODE genetics/Amgen
Mike Frigge: deCODE genetics/Amgen
Andres Ingason: deCODE genetics/Amgen
Askell Love: University of Iceland
Gudmundur L. Norddhal: deCODE genetics/Amgen
Mark Zervas: deCODE genetics/Amgen
Daniel F. Gudbjartsson: deCODE genetics/Amgen
Magnus O. Ulfarsson: deCODE genetics/Amgen
Evald Saemundsen: University of Iceland
Hreinn Stefansson: deCODE genetics/Amgen
Kari Stefansson: deCODE genetics/Amgen

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05595-6

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