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Clinical Application of Whole-Genome Sequencing in Patients with Primary

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Clinical Application of Whole-Genome Sequencing in Patients with Primary Letter to the Editor Clinical application of whole-genome sequenc- Laboratory Improvement Amendments–certified commercial ing in patients with primary immunodeficiency laboratory for NCF2, CYBA, and NCF1 and was negative. Of note, the commercial NCF1 screen examined mutations only in To the Editor: exon 2, which harbors the 2GT deletion that causes most reported Next-generation sequencing, including whole-exome sequenc- cases of NCF1-related chronic granulomatous disease.4 WGS ing and whole-genome sequencing (WES and WGS, respectively), revealed a homozygous 579G>A substitution causing a has been successful at identifying causes of Mendelian diseases, premature stop codon (Trp193X) in NCF1 that had previously even when the condition is seen in a single patient.1-3 Here, been reported as causal for chronic granulomatous disease.5 we report our findings from WGS in 6 patients with primary Patient 3 was a boy who developed Pneumocystis jiroveci immunodeficiency from 5 families in whom the molecular defect pneumonia during the first year of life. There was no family was unknown. history of primary immunodeficiency. Immune evaluation Patients 1 and 2 were full sisters with a history of recurrent demonstrated absent serum IgG and IgA. He had normal numbers infections, including tuberculous lymphadenitis, granulomas, and of B, T, and natural killer (NK) cells by flow cytometry and had pneumonias. They had a similarly affected brother. Both patients normal T-cell proliferative responses to mitogens and antigens. had an absent rhodamine-based respiratory burst, confirming the However, the patient lacked any detectable expression of CD40 diagnosis of chronic granulomatous disease. The parents are ligand (CD154) on T cells after stimulation with ionomycin and distant relatives. Genetic testing was performed at a Clinical phorbol myristate acetate, consistent with a diagnosis of X-linked FIG 1. Semi-quantitative PCR and quantitative real-time PCR results of minigene expression. A, Minigene-1 (IVS111G>T) mRNA expression. B, Quantitative Taqman results showing only 16% expression of the WT mRNA in Minigene-1. C, Minigene-5 (IVS512T>A) mRNA expression. D, Sanger sequencing confirmation of IVS512T>A, resulting in exon 5 skipping. GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. 1 2 LETTER TO THE EDITOR J ALLERGY CLIN IMMUNOL nnn 2015 hyper-IgM syndrome. CD40 ligand gene sequencing was performed at a Clinical Laboratory Improvement Amendments– certified laboratory and no mutations were found, somewhat conflicting with the CD40L expression results. WGS revealed a novel G>T nucleotide substitution in the CD40 ligand gene on the X-chromosome, resulting in a premature stop codon at Glu-230 (Glu230X). 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. Patient 4 was a girl who presented in infancy with a history of failure to thrive and recurrent infections. Flow cytometry showed that she had no T or B cells, but had an elevated percentage of NK cells. T-cell proliferation studies showed no responses to mitogens. A diagnosis of severe combined immunodeficiency (SCID) was made. RAG1 and RAG2 genes were sequenced, and no mutations were identified. WGS revealed a homozygous 82-kb deletion spanning exons 1 to 4 in DCLRE1C (see Fig E1, A, in this article’s Online Repository at www.jacionline.org). Patient 5 was a girl who presented in infancy with failure to thrive and recurrent infections. Immune studies showed absent T cells and B cells and no T-cell proliferative responses to mitogens. All her lymphocytes were NK cells. These findings led to a diagnosis of SCID. Gene sequencing was performed at a Clinical Laboratory Improvement Amendments–certified commercial laboratory for RAG1, RAG2, and DCLRE1C, which are known to be associated with NK-phenotype SCID,8,9 and the results were negative. WGS revealed a novel heterozygous single nucleotide variant observed at an essential splice site in DCLRE1C. This splice site mutation (c.36212T>A) is absent in controls and in EVS, and is predicted to destroy the canonical splice donor site in intron 5. A splice site variant at the FIG 2. DCLRE1C protein assays. A, FLAG-tag insertion in exon 14 of the WT- neighboring nucleotide position (c.36211G>T) is associated DCLRE1C construct and exon 6 of the Dexon5 construct. B, Semi-quantitative with SCID.9 Further investigation revealed an 82-kb deletion PCR showing the presence of Dexon5 mRNA expression. C, Immunoblotting showing the absence of DCLRE1C protein expression in mutant Dexon5 involving exons 1 to 4 in DCLRE1C (see Fig E1, B). The isoform. GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. combined presence of this partial deletion and the c.36212T>A (IVS512T>A) splice site mutation is the likely cause of SCID in this patient. resulted in miscalling of the single nucleotide variant as Patient 6 was a girl whose brother had combined immunode- homozygous. ficiency with a predominance of NK cells. She was investigated The difference in disease severity between patients 5 and 6 is immunologically at an early age and had normal T-lymphocyte interesting because both patients are compound heterozygotes for proliferative responses to mitogens, antigens, and allogeneic similar deletion but have different essential splice site mutations. cells. She did well clinically until around age 7 years, when she Patient 5 had no T-cell function, while patient 6 had normal T-cell became profoundly lymphopenic and developed very low T-cell function until around age 7 years. To explain the difference in function. WGS showed a homozygous essential splice site phenotypic severity, we constructed minigenes for each of the 2 mutation (c.10911G>T) (IVS111G>T) in DCLRE1C that newly identified DCLRE1C variants (IVS111G>T and IVS512 was absent in controls. This single nucleotide variant is extremely T>A) (see Fig E2 in this article’s Online Repository at www. rare (minor allele frequency 5 0.00023 in EVS). This splice site jacionline.org). A decrease in the wild type DCLRE1C mutation is predicted to destroy the canonical splice donor site in (WT-DCLRE1C) isoform was observed in the IVS111G>T intron 1. However, given the rarity of this variant and the lack of variant construct (Fig 1, A). Follow-up quantitative RT-PCR of consanguinity in the family, homozygosity was considered the wild-type and mutant minigene transcript revealed that the unlikely. Deletion screening showed that the patient also had variant produced only 16% of the wild-type transcript (Fig 1, the same 82-kb hemizygous deletion involving exons 1 to 4 of B). The IVS512T>A variant construct resulted in a novel DCLRE1C observed in patient 5 (see Fig E1, C), which had isoform in which exon 5 was skipped (Fig 1, C and D). Both novel J ALLERGY CLIN IMMUNOL LETTER TO THE EDITOR 3 VOLUME nnn, NUMBER nn isoforms are predicted to result in abnormal gene and/or protein Medical Center, cthe Center for Human Genome Variation, Duke University School d expression and/or function. We examined the mRNA and protein of Medicine, and the Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC; eHamad Medical Corporation, Doha, expression of the full-length WT-DCLRE1C cDNA and the Qatar; fthe Department of Immunology, Duke University School of Medicine, IVS512T>A isoform, in which exon 5 is skipped, using Durham, NC; gEshelman School of Pharmacy, University of North Carolina, Chapel FLAG-tagged constructs (Fig 2, A). Although both isoforms Hill, NC; and hInstitute for Genomic Medicine, Columbia University Medical Center, showed similar expression at the mRNA level, only the New York, NY. E-mail: [email protected]; [email protected]. Or: wild-type isoform showed a detectable level of protein (Fig 2, [email protected]. This work was supported by the National Institutes of Health (grants T32 HD43029 and B and C). T32 AI7062 provided support for T.M. during his fellowship training at Duke Univer- Hence, the IVS111G>T variant found in patient 6 produced sity Medical Center) and a Clinical Immunology Society/Grifols Senior Fellowship some of the canonical wild-type isoform, suggesting that this Award (to T.M.). The collection of control samples and the production of sequence mutation decreases the splicing efficiency. The IVS512T>A data were funded in part by the National Institute of Allergy and Infectious Diseases (NIAID) grant UO1AIO67854 (Center for HIV/AIDS Vaccine Immunology variant from patient 5 did not produce any wild-type isoform, [‘‘CHAVI’’]). but did produce another isoform. This result is consistent with Disclosure of potential conflict of interest: T. Mousallem has received funding from the a model in which patient 6 produced enough wild-type Clinical Immunology Society. T. J. Urban is employed by the University of North Car- Artemis protein to delay the onset of the patient’s combined olina at Chapel Hill, which has received or has grants pending from the National In- immunodeficiency, resulting in a less severe phenotype. stitutes of Health (NIH). B. Krueger has received consultancy fees from LabCorp and Gerson Lehrman Group. R. E. Parrot and R. H. Buckley are employed by the Duke The use of next-generation sequencing is accepted for University Medical Center, which has received or has grants pending from Baxter investigating undiagnosed genetic conditions. Here, we show Healthcare and has received funding from the NIH. J. L. Roberts is employed by the value of WGS in patients with primary immunodeficiency the Duke University Medical Center and has received compensation for delivering without identified causal mutations.
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