Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: BCL11B

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:55 a.m. | Last Modified: 11 Oct 2023, 11:55 a.m.

Panel Version: 4.174

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Rebecca Tooze (University of Oxford), there is sufficient number of cases (both published and unpublished) and supporting functional evidence for this gene to be promoted to GREEN in the next GMS update.

Created: 7 May 2023, 5:56 a.m. | Last Modified: 7 May 2023, 5:56 a.m.

Panel Version: 4.14

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, OMIM:618092; Craniosynostosis, MONDO:0015469

Publications

• 31067316
• 34900871
• 36275064
• 36470856
• 36512050
• 36980886

Green List (high evidence)

• Mosaic frameshift from the 100kGP data was identified (see article by Tooze et al., doi:10.3390/genes14030615), encoding a 28 bp insertion.
• Three other cases are known [unpublished]: c.2438_2459del; (p.Val813Alafsı24); 14qdel GRch37 arr 14q32.2(96,723,247-100,938,073)x1; Deletion arr[hg19]14q32.2(99,052,763-100,591,634)x1.
• A de novo substitution was described in BCL11B (c.7C>A; p.(Arg3Ser)) and functionally characterised in a mouse model. The variant caused loss of interaction with transcriptional complexes and craniosynostosis (Goos et al., 2019).
• A patient was described with a de novo frameshift variant in BCL11B, identified by whole-exome sequencing: c.2346_2361del; p.(Gly783Alafs*24) (Zhao et al., 2022).
• An additional de novo loss of function variant has been described in a patient with developmental delay and craniosynostosis: c.2439_2452dup; p.(His818Argfs*31) (Eto et al., 2022).


In total, 7 families are known or described with variants in BCL11B and confirmed craniosynostosis.

Created: 2 Mar 2023, 1:39 p.m. | Last Modified: 2 Mar 2023, 1:39 p.m.

Panel Version: 3.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan.
Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited.
The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins.

31067316 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis.
Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes.
Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7.
introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures.

34900871 Gaillard et al, 2021, 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6.

36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient.

36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs).

Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken.

4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature.
Sources: Expert list

Created: 17 Jan 2023, 1:52 p.m. | Last Modified: 17 Jan 2023, 1:53 p.m.

Panel Version: 3.1

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Craniosynostosis and global developmental delay

Publications

• 36275064
• 310673176
• 34900871
• 36512050
• 36470856