2. Academic Validation
  3. Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

  • N Engl J Med. 2016 Dec 1;375(22):2165-2176. doi: 10.1056/NEJMoa1509164.
Divya Punwani 1,  Yong Zhang 1,  Jason Yu 1,  Morton J Cowan 1,  Sadhna Rana 1,  Antonia Kwan 1,  Aashish N Adhikari 1,  Carlos O Lizama 1,  Bryce A Mendelsohn 1,  Shawn P Fahl 1,  Ajithavalli Chellappan 1,  Rajgopal Srinivasan 1,  Steven E Brenner 1,  David L Wiest 1,  Jennifer M Puck 1
Affiliations

Affiliation

  • 1 From the Department of Pediatrics, University of California, San Francisco (UCSF), School of Medicine and UCSF Benioff Children's Hospital (D.P., J.Y., M.J.C., A.K., B.A.M., J.M.P.), and the Cardiovascular Research Institute, UCSF (C.O.L.), San Francisco, and the Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley (A.N.A., S.E.B.) - all in California; the Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia (Y.Z., S.P.F., D.L.W.); and Innovation Labs, Tata Consultancy Services, Telangana, India (S.R., A.C., R.S.).
PMID: 27959755 DOI: 10.1056/NEJMoa1509164
Abstract

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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