Editors' ChoiceImmunodeficiency

Screen and you shall find

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Science Translational Medicine  14 Dec 2016:
Vol. 8, Issue 369, pp. 369ec199
DOI: 10.1126/scitranslmed.aal3697

One of the most significant public health advances of the past 50 years has been newborn screening, which enables early diagnosis of treatable diseases, such as phenylketonuria or sickle cell anemia, before affected infants suffer irreversible injury or death. A recently implemented newborn screening test detects T cell receptor excision circles (TRECs), small segments of DNA excised during T cell receptor rearrangement in T cell development. Newborns without TRECs in their peripheral blood likely have severe combined immunodeficiency (SCID); with early identification, they can undergo lifesaving hematopoietic stem cell transplant (HSCT) to prevent death from overwhelming infection in the first months of life.

Punwani and colleagues report an infant with a novel SCID-causing mutation identified through newborn screening. Puzzlingly, this patient also had craniofacial malformations, severe neurological impairment, and abnormal skin, which are typically not seen in SCID. Using whole-exome sequencing, the researchers identified a candidate point mutation in one of the baby’s BCL11B alleles known to be important for lymphocyte development. The research team introduced the point mutation into zebrafish embryos, recapitulating the lymphocyte deficiencies, craniofacial malformations, and neuronal migration abnormalities. They found that the mutated BCL11B protein had a dominant negative effect on transcription of genes important for T cell development, yet it induced transcription of another gene potentially related to the cranial and brain malformations. While the wild-type protein rescued a bcl11b knockdown zebrafish, the mutated protein did not rescue the knockdown phenotype. As for the patient, HSCT cured his immunodeficiency, but his malformations and neurological disease persist.

This child’s diagnosis depended on three components: newborn screening for a rare disease, astute clinicians who recognized the unusual features of this case, and access to powerful scientific tools that identified and characterized this novel mutation. In turn, the diagnosis led to a greater understanding of the mutated gene’s function. With newborn screening expansion and ready availability of whole-exome sequencing for unusual clinical phenotypes, we can expect more such discoveries in the future.

D. Punwani et al., Multisystem anomalies in severe combined immunodeficiency with mutant BCL11B. N. Engl. J. Med. 10.1056/NEJMoa1509164 (2016). [Abstract]

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