Clinical application of whole-genome sequencing in patients with primary immunodeficiency

Of note, the commercial NCF1 screen examined mutations only in exon 2, which harbors the 2GT deletion that causes most reported cases of NCF1-related chronic granulomatous disease.4 WGS revealed a homozygous 579G>A substitution causing a premature stop codon (Trp193X) in NCF1 that had previously been reported as causal for chronic granulomatous disease.5 Patient 3 was a boy who developed Pneumocystis jiroveci pneumonia during the first year of life. Nonsense mutations in neighboring codons (G227X and Q232X) have been previously reported as causes of X-linked hyper-IgM syndrome.6,7 Based on the mutation's absence in control subjects and in Exome Variant Server (EVS; National Heart, Lung, and Blood Institute GO Exome Sequencing Project, Seattle, Wash; http://evs.gs.washington.edu/EVS/), its predicted functional consequence, and the described disease-causing mutations in neighboring codons, this mutation was judged the likely cause of this patient's immune defect.