MAP1B mutations cause intellectual disability and extensive white matter deficit

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.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). 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.We are grateful to the participants and we thank the psychologists, nurses and staff, in particular Berglind Eiriksdottir, at the Research Recruitment Center and technicians and staff at Röntgen Domus. We also thank the staff at deCODE genetics core facilities and all our colleagues for their important contribution to this work. L.J. received support from the Swedish Society of Medicine, the Swedish Brain Foundation and Swedish Society for Medical Research. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreements’ no. 115008 (NEWMEDS) and no. 115300 (EUAIMS) of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007-2013), EU-FP7 funded grant no. 602450 (IMAGEMEND) and EU funded FP7-People-2011-IAPP grant agreement no. 286213 (PsychDPC).Peer Reviewe

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

Publisher's version (útgefin grein) Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chipgenotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.We wish to thank the family of the two probands, as well as all the other individuals who participated in the study and whose contribution made this work possible.Peer Reviewe