Description of pathogenic variants in the NADPH oxidase genes of Mexican patients with chronic granulomatous disease

* Introduction: Chronic granulomatous disease (CGD) is an inborn error of immunity secondary to an inability of phagocytes to produce reactive oxygen species.
* Methods: We summarize the genetic features of 115 CGD patients diagnosed in Mexico from 2011 to 2023; the patients were recruited from thirteen hospitals from all over Mexico. We described the different pathogenic variants in patients with CGD and performed a statistical analysis to evaluate the association between CYBB and autosomal recessive genes, and between different types of CYBB gene pathogenic variants.
* Results: We identify the mutated gene in 115 patients from 99 kindreds. 88 (76.5%) patients had XL-CGD and 27 (23.4%) had AR-CGD. Hemizygous mutations of CYBB were nonsense (n=32), missense (n=19), small deletion (n=17), small insertion (n=4), essential splicing site (n=7), deletion/insertion (n=1), and promoter site (n=1) mutations. Seven patients had CNVs corresponding to a large deletion encompassing the region including the CYBB gene. Other mutations were found in autosomal genes: NCF1 (n=7, 6%), NCF2 (n=15 ,13%), and CYBA (n=5, 4%). Biallelic NCF2 mutations, corresponding to homozygous mutations (nonsense n= 6, missense n=1, splice site n=2, gain n=1, and deletion n=3) and two compound heterozygous mutations (deletion+missense; deletion+nonsense). Homozygous CYBA mutations were essential (splicing site n=1, missense n=2, and deletion n=2). No mutations were identified in NCF4 or CYBC1. We found two novel mutations (c.175del, c.141+1G>C) In total, 55 patients died. Mortality was higher in patients with XLCGD (52.3%; n=45) than in patients with AR-CGD (20%; n=5), (p=0.004), with no difference in type of mutation in CYBB.
* Conclusions: The x-linked form is the most frequent in our mixed and outbred population, this form has higher mortality, therefore, hematopoietic cell transplantation should be considered. The most frequent variant in the CYBB gene is nonsense form. The most frequent AR form gene is NCF2.

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