Case report: A novel truncating variant of BCL11B associated with rare feature of craniosynostosis and global developmental delay

Abstract

Craniosynostosis is a premature fusion of cranial sutures, resulting in abnormally shaped skull and brain development disorder. The description of craniosynostosis in patients with BCL11B mutations is rare. Here, we firstly report a 25-month-old Chinese boy with a novel frameshift variant in BCL11B gene. The patient was identified c.2346_2361del by whole-exome sequencing and was confirmed to be de novo by parental Sanger sequencing. This patient presented clinical phenotype of craniosynostosis as well as global developmental delay. He had a small mouth, thin upper lip, arched eyebrows, a long philtrum, midfacial hypoplasia and craniosynostosis. Brain MRI showed brain extracerebral interval and myelination changes, and brain CT with 3D reconstruction showed multi-craniosynostosis. Our study expands the clinical phenotypes of patients with BCL11B gene mutation, and our findings may help guide clinical treatment and family genetic counseling.

Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape

“…Importantly, gain-of function coding variants in RUNX2 were reported in patients with midline craniosynostosis and the RUNX2 p.Ala84-Ala89del variant was reported to be significantly enriched in sagittal NCS, implicating overexpression of this gene in the etiology of craniosynsotosis 102 . We also identified BCL11B, a transciption factor involved in keeping suture patency by preventing expression of RUNX2 and FGFR2 in the suture mesenchyme 103 and for which de novo mutations have been observed in several craniosynostosis cases 104,105 . In addition, we identified PTHLH, whose associated receptor gene, PTH2R is implicated in syndromic craniosynostosis 106 .…”

Joint Multi-Ancestry and Admixed GWAS Reveals the Complex Genetics behind Human Cranial Vault Shape

“…Importantly, gain-of function coding variants in RUNX2 were reported in patients with midline craniosynostosis and the RUNX2 p.Ala84-Ala89del variant was reported to be significantly enriched in sagittal CS, implicating overexpression of this gene in the etiology of craniosynsotosis 99 . We also identified BCL11B, a transciption factor involved in keeping suture patency by preventing expression of RUNX2 and FGFR2 in the suture mesenchyme 100 and for which de novo mutations have been observed in several craniosynostosis cases 101,102 . In addition, we identified PTHLH, whose associated receptor, PTH2R is implicated in syndromic craniosynostosis 103 .…”

Pivotal role of BCL11B in the immune, hematopoietic and nervous systems: a review of the BCL11B-associated phenotypes from the genetic perspective

“…This truncated protein would lack the last three C2H2 zinc-finger domains and hence affect the protein´s function in binding to its target DNA. However, the authors recommend further experiments to elucidate the true mechanisms of action of the variant [ 38 ].…”

“…In humans, both de novo and inherited mutations result in complex syndromes combining craniosynostosis with immunodeficiency [ 6 ], dysmorphic features, or neurodevelopmental delay [ 37 – 39 ]. The mutations in these patients act by disrupting the binding of the protein to its target DNA, which results in haploinsufficiency [ 38 , 39 ] or redirecting the protein binding to novel sites [ 6 ].…”