BCL11B-related disease: a single phenotypic entity?

Abstract

Craniosynostosis (CRS), the premature fusion of sutures between the skull bones, is characterised by a long "tail" of rare genetic diagnoses. This means that pathogenic variants in many genes are responsible for a minority of cases, and identifying these disease genes and delineating the associated phenotype is extremely important for patient diagnosis and for genetic counselling of families. One such gene is BCL11B. Heterozygous pathogenic variants in BCL11B have been described as causative for two Mendelian phenotypes, but until recently the gene remained only marginally associated with CRS. We have carried out a systematic review of literature, providing evidence that BCL11B-related disease (BRD) should be regarded as a single phenotypic entity. Furthermore, we describe four new patients, all of whom presented with CRS, thus expanding the phenotype of BRD and highlighting CRS as an important diagnostic clue.

Fig. 1. Pre-operative images of 3D CT scans of Patients 1-4.

Patient 1 (1A–1D), Patient 2 (2A–2D), Patient 3 (3A–3D) and Patient 4 (4A–4D). The red arrows indicate prematurely fused sutures.

Fig. 2. Facial phenotype of Patients 2, 3 and 4.

1) Patient 2 at 12 months (1A–1D) and 3 years (1E). Note thin eyebrows, long/smooth philtrum and thin upper lip vermilion; 2) Patient 3 at 3 months (2A–2D) and 11 years (2E–2H). Facial features include asymmetry, thin palpebral fissures, thin/sparse eyebrows, long/smooth philtrum, and thin upper lip vermilion; 3) Patient 4 at 6 months (3A–3D) and 3 years (3E–3H). The phenotype comprises facial asymmetry, thin/sparse eyebrows, depressed nasal bridge, long/smooth philtrum, thin upper lip vermilion.

Fig. 3. Structure and variants in BCL11B.

A Representation of BCL11B. Coding regions are in red. Note the disproportionate size of exon 4. B Representation of BLC11B with exons out of scale, demonstrating the location of important functional domains (coloured boxes). All the zinc-finger domains are located within exon 4. C BCL11B protein (894 amino acids) with the pathogenic variants reported in the literature. Variants below the protein are present in patients with CRS. Variants in green were identified in our cohort. Different shapes represent different variant types (star, frameshift; triangle, splice site; circle, nonsense; square, missense).

Fig. 4. Deletions encompassing BCL11B.

Genes in the region are represented in red. The deletion identified in Patient 3 is shown in purple. Patients from the literature and/or Decipher are represented in green. Bars with a hatched pattern indicate that CRS was present in that patient. The two black arrows indicate that these deletions extend beyond the picture frame.