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Nat Commun. 2018 Oct 25;9(1):4447. doi: 10.1038/s41467-018-06964-x.

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

Author information

1
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
2
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
3
Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
4
The Medical Center, Glaesibae, Reykjavik, Iceland.
5
Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland.
6
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
7
Children's Hospital Iceland, Landspitali University Hospital, Reykjavik, Iceland.
8
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. patrick.sulem@decode.is.
9
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. kari.stefansson@decode.is.
10
Faculty of Medicine, University of Iceland, Reykjavik, Iceland. kari.stefansson@decode.is.

Abstract

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 chip-genotyped 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.

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