Nijmegen Breakage Syndrome Detected by Newborn Screening for T Cell Receptor Excision Circles (TRECs)

Patel, Jay P.; Puck, Jennifer M.; Srinivasan, R.; Brown, Christina; Sunderam, Uma; Kundu, Kunal; Brenner, Steven E.; Gatti, Richard A.; Church, Joseph A.

doi:10.1007/s10875-015-0136-6

Cited by 26 publications

(17 citation statements)

References 31 publications

(38 reference statements)

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“…The protocol was approved by the institutional review board at the University of California, San Francisco. Genomic DNA from blood was subjected to whole-exome sequencing and analysis 7 (see the Methods section in the Supplementary Appendix, available with the full text of this article at NEJM.org). The patient’s BCL11B variant was confirmed by Sanger sequencing of DNA from blood and buccal brushings and was found to be a de novo mutation (it was not present in the DNA of either parent).…”

Section: Methodsmentioning

confidence: 99%

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Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

Punwani¹,

Zhang

Yu³

et al. 2016

N Engl J Med

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102

106

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BACKGROUND Severe combined immunodeficiency (SCID) is characterized by arrested T-lymphocyte production and by B-lymphocyte dysfunction, which result in life-threatening infections. Early diagnosis of SCID through population-based screening of newborns can aid clinical management and help improve outcomes; it also permits the identification of previously unknown factors that are essential for lymphocyte development in humans. METHODS SCID was detected in a newborn before the onset of infections by means of screening of T-cell–receptor excision circles, a biomarker for thymic output. On confirmation of the condition, the affected infant was treated with allogeneic hematopoietic stem-cell transplantation. Exome sequencing in the patient and parents was followed by functional analysis of a prioritized candidate gene with the use of human hematopoietic stem cells and zebrafish embryos. RESULTS The infant had “leaky” SCID (i.e., a form of SCID in which a minimal degree of immune function is preserved), as well as craniofacial and dermal abnormalities and the absence of a corpus callosum; his immune deficit was fully corrected by hematopoietic stem-cell transplantation. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The resulting BCL11B protein had dominant negative activity, which abrogated the ability of wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration; this revealed a previously unknown function of BCL11B. The patient’s abnormalities, when recapitulated in bcl11ba-deficient zebrafish, were reversed by ectopic expression of functionally intact human BCL11B but not mutant human BCL11B. CONCLUSIONS Newborn screening facilitated the identification and treatment of a previously unknown cause of human SCID. Coupling exome sequencing with an evaluation of candidate genes in human hematopoietic stem cells and in zebrafish revealed that a constitutional BCL11B mutation caused human multisystem anomalies with SCID and also revealed a prethymic role for BCL11B in hematopoietic progenitors. (Funded by the National Institutes of Health and others.)

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Section: Methodsmentioning

confidence: 99%

“…2 In addition to enhancing the efficacy of treatment, 2,3 newborn screening can reveal previously unknown causes of T-cell lymphopenia. 1,4–7 …”

mentioning

confidence: 99%

Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

Punwani¹,

Zhang

Yu³

et al. 2016

N Engl J Med

Self Cite

102

106

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“…1 A ) was subjected to WES (HiSeq2500; Illumina) and analysis to identify nonsynonymous, rare variants present in both affected siblings. Read alignment and variant calling were performed using a previously described protocol ( Patel et al, 2015 ). The variants were reconfirmed with updated software versions BWA version 0.7.10 for read mapping and GATK version 3.1–1 for base quality score recalibration, realignment around known indels, variant calling, and variant quality score recalibration.…”

Section: Methodsmentioning

confidence: 99%

A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70

Chan

Punwani

Kadlecek

et al. 2016

Journal of Experimental Medicine

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“…It has been demonstrated that at least some NBS patients can be detected via neonatal T-cell excision circles (TRECs) screening (7). Also, low kappa-deleting recombination excision circle (KREC) numbers have been reported in NBS (8).…”

Section: Introductionmentioning

confidence: 99%

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

et al. 2017

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BackgroundNijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Due to the rarity of the disease in the rest of the world, studies of NBS patients are few. Here, we report a prospective study of a cohort of Russian NBS patients.Methods35 Russian NBS patients of ages 1–19 years, referred to our Center between years 2012 and 2016, were prospectively studied.ResultsDespite the fact that in 80% of the patients microcephaly was diagnosed at birth or shortly thereafter, the average delay of NBS diagnosis was 6.5 years. Though 80% of the patients had laboratory signs of immunodeficiency, only 51% of the patients experienced significant infections. Autoimmune complications including interstitial lymphocytic lung disease and skin granulomas were noted in 34%, malignancies—in 57% of the patients. T-cell excision circle (TREC)/kappa-deleting recombination excision circle (KREC) levels were low in the majority of patients studied. Lower KREC levels correlated with autoimmune and oncological complications. Fifteen patients underwent hematopoietic stem cell transplantation (HSCT), 10 of them were alive and well, with good graft function. Three patients in the HSCT group and five non-transplanted patients died; tumor progression being the main cause of death. The probability of the overall survival since NBS diagnosis was 0.76 in the HSCT group and 0.3 in the non-transplanted group.ConclusionBased on our findings of low TRECs in most NBS patients, independent of their age, TREC detection can be potentially useful for detection of NBS patients during neonatal screening. KREC concentration can be used as a prognostic marker of disease severity. HSCT is a viable treatment option in NBS and should be especially considered in patients with low KREC numbers early on, before development of life-threatening complications.

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Nijmegen Breakage Syndrome Detected by Newborn Screening for T Cell Receptor Excision Circles (TRECs)

Cited by 26 publications

References 31 publications

Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

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