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.
Highlights
Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders
We used a family-based approach to find a LoF variant in microtubule-associated protein 1B (MAP1B) that associates with ID, grey matter (GM) and white matter (WM) deficits and lower fractional anisotropy (FA)
Two additional stop-gain variants in MAP1B were found, in two independent families, which confirmed the association with cognitive impairments
Summary
Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Wholegenome 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). We show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons. 6 Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik 101, Iceland. Large-scale next-generation sequencing efforts of individuals with developmental disorders[7], ID8,9 and ASD10 have made significant contributions to the understanding of their pathogenesis. Utilising next-generation sequencing to search for variants in genes important for brain development and function combined with psychological assessment and brain structural traits in carriers, could provide a better understanding of the molecular processes and neuronal connectivity underlying cognitive diversity in neurodevelopmental disorders. Carriers have significantly less white matter (WM) volume and a decrease in fractional anisotropy (FA), suggesting disordered or compromised axons
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
