Immunodeficiency 49

A number sign (#) is used with this entry because of evidence that immunodeficiency-49 (IMD49) is caused by heterozygous mutation in the BCL11B gene (606558) on chromosome 14q32.

Heterozygous mutation in the BCL11B gene can also cause intellectual developmental disorder with speech delay, dysmorphic facies, and T cell abnormalities (IDDSFTA; 618092), which has overlapping features.

Clinical Features

Punwani et al. (2016) reported a male infant, born of unrelated parents, who was found by newborn screening to have severe T cell lymphopenia. The screening test was quantification of blood levels of T-cell-receptor (TCR) excision circles (TRECs), which are DNA by-products of TCR rearrangement that indicate production of naive T cells. The results in this infant showed no detectable TRECs and profound T-cell lymphopenia. Immunologic studies revealed a SCID T-, B+, NK+ phenotype, with no naive CD4+ helper T cells and impaired T-cell proliferative responses. The patient underwent successful hematopoietic stem cell transplantation. In addition to a primary immunodeficiency, the patient had multiple abnormal systemic features, including neonatal teeth, hypotonia, umbilical hernia, pulmonary artery stenosis, hirsutism, wormian skull bones, and erythematous psoriasiform dermatitis. Dysmorphic facial features included micrognathia, hypertelorism, and short palpebral fissures. At age 2 years, he had intellectual disability, spastic quadriplegia, and seizures. He could smile and track faces and objects, but had no language and could not sit. Brain imaging showed agenesis of the corpus callosum, abnormal ventricles, malrotated hippocampi, volume loss of white matter and lentiform nuclei, and T2-weighted hyperintensities in the caudate nuclei.

Lessel et al. (2018) reported a 2-year-old boy (patient E) with IMD49 who had a phenotype similar to that of the patient reported by Punwani et al. (2016). Soon after birth, he was noted to have diffuse skin abnormalities characterized as congenital erosive dermatitis associated with leukopenia and eosinophilia. Laboratory studies showed low T-cell receptor excision circles (TRECs) suggestive of SCID. However, repeated T-cell counts over time were inconsistent with this diagnosis. The patient had dysmorphic features, including myopathic facies, bitemporal narrowing, short philtrum, small and upslanted palpebral fissures, prominent nose, small mouth with downturned corners, micrognathia, posteriorly rotated ears, and abnormal dentition. He had hypotonia and severe global developmental delay. At age 2 years, he was unable to sit or stand and could not speak.

Molecular Genetics

In a male infant with IMD49, Punwani et al. (2016) identified a de novo heterozygous missense mutation in the BCL11B gene (N441K; 606558.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies demonstrated that BCL11B induced human hematopoietic stem cells to commit to the T-cell lineage; ectopic expression of the N441K mutation abrogated T-cell development. Expression of the N441L mutant into zebrafish reproduced abnormalities observed with knockdown of the bcl11b gene; conversely, expression of the mutant into zebrafish with bcl11b knockdown failed to rescue the T-cell developmental and craniofacial defects observed in mutant animals. These findings were consistent with a dominant-negative effect. The mutant protein was shown to form a nonfunctional heterodimer with wildtype BCL11B, which had reduced binding to known canonical DNA promoter sites as well as increased abnormal binding to novel sites not recognized by the wildtype protein. Exome sequencing analysis also identified variants in several other genes in the patient, including NLRP1 (606636), USO1 (603344), and CAPNS1 (114170).

In a 2-year-old boy (patient E) with IMD49, Lessel et al. (2018) identified a de novo heterozygous missense mutation in the BCL11B gene (N807K; 606558.0002). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but based on the studies of the N441K mutation (606558.0001) by Punwani et al. (2016), the N807L mutation was predicted to result in a gain of function.

Animal Model

In zebrafish, Punwani et al. (2016) found that bcl11b regulates the positioning and movement of hematopoietic thymic progenitor cells from the bone marrow to the thymus by modulating the expression of chemotactic signal receptors ccr7 (600242) and ccr9 (604738). Morpholino knockdown of the bcl11b gene in zebrafish blocked the development of T-cell progenitors and caused other developmental changes, including craniofacial abnormalities.