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Punwani D , Zhang Y , Yu J , Cowan MJ , Rana S , Kwan A , Adhikari AN , Lizama CO , Mendelsohn BA , Fahl SP , Chellappan A , Srinivasan R , Brenner SE , Wiest DL , Puck JM
Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B
N Engl J Med. 2016 Dec;375(22) :2165-2176
PMID: 27959755    PMCID: PMC5215776    URL: https://www.ncbi.nlm.nih.gov/pubmed/27959755
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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.).
1533-4406 Punwani, Divya Zhang, Yong Yu, Jason Cowan, Morton J Rana, Sadhna Kwan, Antonia Adhikari, Aashish N Lizama, Carlos O Mendelsohn, Bryce A Fahl, Shawn P Chellappan, Ajithavalli Srinivasan, Rajgopal Brenner, Steven E Wiest, David L Puck, Jennifer M R13 AI094943/AI/NIAID NIH HHS/United States R01 AI078248/AI/NIAID NIH HHS/United States U54 AI082973/AI/NIAID NIH HHS/United States R01 AI105776/AI/NIAID NIH HHS/United States R21 AI111208/AI/NIAID NIH HHS/United States Case Reports Journal Article United States N Engl J Med. 2016 Dec;375(22):2165-2176.