Duplication of Exons 7-8 in NCF2 leads to severe to asymptomatic spectrum in Chronic Granulomatous Disease.

INTRODUCTION. Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI). It is characterized by infections and inflammation in different organs. The genes responsible for CGD described to date are CYBB, CYBA, NCF1, NCF2, NCF4 and CYBC1 In the NCF2 gene, 104 different allelic mutations have been described, such as deletions, nonsense, splice site, missense, insertions and indels. New genetic tools, such as next generation sequencing, offer the detection of the copy number variations (CNV). We describe a family with CGD due to a homozygous duplication in exons 8 and 9 of NCF2.
CASE PRESENTATION. An 11-year-old male patient (P1), member of a consanguineous family with low socioeconomic status, debuted with hepatic abscesses, Chron’s colitis and multiple pneumonias. Dihydrorhodamine (DHR) test showed chronic granulomatous disease. The expression of p67phox was null. Sanger sequencing of the NCF2 gene did not show the responsible mutation, however, through next-generation sequencing (NGS), we found a homozygous duplication encompassing exons 8 to 9. We proceeded to pedigree, both parents were heterozygous (c.dup8-9/WT); his 12-year-old older brother (P2) was homozygous (c.dup8-9/dup8-9). DHR showed CGD; in addition, p67phox expression in neutrophils was null. Surprisingly P2 only referred two events of cervical adenitis with spontaneous remission.
CONCLUSIONS. We present two patients from a family with CGD secondary to a homozygous duplication in NCF2. This is the third case reported internationally with CNVs in the NCF2 gene. The clinical spectrum of this pathogenic variant is from asymptomatic to severe. The P2 was found by pedigree testing, which highlights its importance even in asymptomatic relatives. To our knowledge, no case of asymptomatic CGD with CNV in NCF2 has been described.

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