Atlassian uses cookies to improve your browsing experience, perform analytics and research, and conduct advertising. Accept all cookies to indicate that you agree to our use of cookies on your device. Atlassian cookies and tracking notice, (opens new window)
Zhao et al, 2022, PMID: 36275064: 25 month old Chinese male w/ craniosynostosis, global developmental delay (ID, speech impairment, motor delay, abnormal brain MRI), small mouth, thin upper lip, arched eyebrows, a long philtrum, midfacial hypoplasia, increased IgE. Identified by whole exome sequencing. De novo determined by Sanger sequencing. 1 point (common, NMD-, de novo).
Occurs in exon 4/4, NMD is not predicted. 111/894 amino acids removed (12.4%).
Present in 1 allele in gnomAD v4.
P in ClinVar by Children’s Hospital of Fudan University (same as PMID: 36275064) and University Hospital Muenster. Both submissions state that the individual was affected and that the variant was de novo. The submission from UHM says that this was a 10-19yo male with Global developmental delay, Trigonocephaly (subtype of craniosynostosis), Obesity, Sleep abnormality, EEG abnormality, Impulsivity. 0.5 points (common, NMD-, de novo, removed 0.5 points due to lack of information about how the variant was ascertained).
NM_138576.4(BCL11B_v001): c.2439_2452dup [p.(His818Argfs*31)] - 1 point
Eto et al, 2022, PMID: 36470856: 5 yo Japanese male with developmental delay, early craniosynostosis, and distinctive features including forehead protrusion, arched eyebrows, flat nose base, thin upper lip, small mouth, long philtrum, retrognathia and low-set ears. Patient also had feeding issues. Variant identified on trio exome sequencing and confirmed by Sanger. 1 point (common, NMD-, de novo).
Occurs in exon 4/4, NMD is not predicted. 76/894 amino acids removed (8.5%).
Absent from gnomAD v4.
LP/VUS in ClinVar by Baylor and Invitae, respectively. Baylor reports patient was affected and variant was de novo, but no clinical features reported.
BCL11B (NM_138576.4) c.2605del p.(Leu869TrpfsTer5) - 1 point
Pande et al, 2023 PMID: 37337996: 1yo female with sagittal suture craniosynostosis and dysmorphic features including low posterior hairline, scaphocephaly, tall forehead, small and down-slanting palpebral fissures, telecanthus, depressed nasal root with convex nasal bridge, low set and anteverted external ears, small earlobes, long and smooth philtrum, thin upper vermilion and a small mouth. She also had microcytic hypochromic anemia and a normal MRI. Variant was identified on trio exome and confirmed de novo, confirmed by Sanger sequencing. 1 point (common, NMD-, de novo).
Occurs in exon 4/4, NMD is not predicted. 25/894 amino acids removed (2.8%)
Pande et al, 2023 PMID: 37337996: 10 month old female with abnormal head shape with brachycephaly, prominent metopic suture and mild proptosis suggestive of craniosynostosis. She also had microcephaly, mid-face retrusion, high arched palate, hirsutism, hypodontia, umbilical hernia and mild hepatomegaly. Pt died at 12 months old due to lower respiratory tract infection with high-grade fever. Variant was identified on trio exome sequencing and confirmed by Sanger, de novo. Pt also carried two other de novo heterozygous variants, c.881G>A p.(Arg294Gln) in exon 10 of KRIT1 (NM_194454.3) and c.328C>Tp.(Arg110Cys) in exon 6 of MORC2 (NM_001303256.3). Authors considered both likely pathogenic. Not scoring this patient due to the presence of other variants.
Occurs in exon 4/4, NMD not predicted, 339/894 amino acids removed (37.9%)
BCL11B (NM_138576.4) c.2443del p.(Arg815GlyfsTer29) - 1 point
Pande et al, 2023 PMID: 37337996: 5 yo male with premature fusion of sagittal suture suggestive of sagittal suture craniosynostosis, ventricular cyst in brain, papular rashes, developmental delay, normochromic normocytic anemia, elevated IgE, abnormal brain MRI, scaphocephaly, tall forehead, low set ears with small ear lobes, high bridge of nose with overhanging columella, long philtrum, thin upper and lower vermillion borders and downturned corners of mouth. Normal microarray. Variant identified on singleton exome sequencing, confirmed de novo by Sanger. 1 point (common, NMD-, de novo).
Occurs in exon 4/4, NMD is not predicted. 79/894 amino acids removed (8.8%)
Absent from GnomAD v4.
P in ClinVar by authors of PMID: 37337996.
BCL11B c.7C>A p.Arg3Ser - 1.1 points
Goos et al 2019, PMID: 31067316: Now 19yo male patient with craniosynostosis, dysmorphic features, impaired vision, seizures, but otherwise healthy and did not present with any extra-craniofacial pathologies. Variant identified by trio WGS, de novo. Authors showed that mice with this variant developed variable and partial, bilateral osteogenic fusion of the coronal suture that was accompanied by narrowing of the sagittal and lambdoid sutures. Homozygous, mutant mice (Bcl11bR3S/R3S) recapitulated perinatal lethality of of Bcl11b−/− mice due to apparent respiratory insufficiency. 1.1 points (missense variant, common, functional data, de novo).
Absent from gnomAD v4.
Absent from ClinVar.
Additional variants not included here:
p.Pro422Leu, p.Gly582Ser, p.Gly667Glu, p.Pro673Arg (all from PMID: 34900871)
Functional studies:
Kyrylkova et al, 2016, PMID: 26453795: Mouse model showing that Bcl11bncc−/− mice exhibit craniosynostosis and variable degree of bone porosity at three weeks of age. 2 points.
PMID: 38472338 - review paper
Variant/Case Evidence: 5.6 points
Segregation Evidence:
Case/Control Evidence:
Experimental Evidence: 2 points
Source:
Clinical ValidityPoints Total
7.6 points (further evidence is available but not reviewed since moderate was reached)
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
At least moderate (further evidence is available but not reviewed since moderate was reached)
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Severity
Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited
BCL11B is associated with autosomal dominant craniosynostosis (PMID: 38472338, 36275064, 36470856, 37337996, 37337996, 31067316, 34900871). Individuals may also have dysmorphic features and/or neurodevelopmental delay. Some individuals have been reported to have feeding difficulties and immune system abnormalities. Both de novo and inherited variants have been reported. BCL11B has also been associated with autosomal dominant severe combined immunodeficiency and autosomal dominant intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities.