Microcephaly
Gene: BRD4
Sufficient individuals with microcephaly to support Green rating on this panel.
Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 1% of patients have mutations in the BRD4 gene.
Olley et al. (2018) report 4 patients with CdLS phenotype with 4 different variants (1 deletion incl BRD4, 1 missense, and 2 frameshift). Alesi et al. (2019) reported a patient with 19p13.12p13.11 deletion including BRD4 with CdLS phenotype.
Olley et al (2021) provided further functional evidence for the previous missense variant, showing it reduces BRD4-occupancy at enhancers it does not affect transcription of the pluripotency network in mouse embryonic stem cells. Rather, it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells.
Houzelstein et al. (2002) showed that mice with heterozygous LOF mutations in Brd4 have marked early postnatal mortality, severe prenatal onset growth failure, abnormalities of the craniofacial skeleton and reduced body fat19; all features common in CdLS.Created: 20 Aug 2021, 12:07 a.m. | Last Modified: 20 Aug 2021, 12:07 a.m.
Panel Version: 1.40
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Cornelia de Lange syndrome 6, MIM# 620568
Publications
PMID: 29379197;
- 4x patients reports however only 3 reported with occipitofrontal circumference of < -3 SD
- 1x microdeletion of 1.04Mb, 1x missense and 1x fs. All de novo
PMID: 30302754
- 1x proband with occipitofrontal circumference 28 cm (−2 SD)
- de novo interstitial deletion involving the shortarm of a chromosome 19, 1.97 Mb in size, which included BRD4Created: 31 Aug 2020, 7:42 a.m. | Last Modified: 31 Aug 2020, 7:42 a.m.
Panel Version: 0.213
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Cornelia de Lange-like syndrome
Publications
Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome, MONDO:0016033 to Cornelia de Lange syndrome 6, MIM# 620568
Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome to Cornelia de Lange-like syndrome, MONDO:0016033
Publications for gene: BRD4 were set to 29379197; 30302754
Gene: brd4 has been classified as Green List (High Evidence).
Gene: brd4 has been classified as Amber List (Moderate Evidence).
Tag SV/CNV tag was added to gene: BRD4.
Phenotypes for gene: BRD4 were changed from to Cornelia de Lange-like syndrome
Publications for gene: BRD4 were set to
Mode of inheritance for gene: BRD4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: brd4 has been classified as Amber List (Moderate Evidence).
gene: BRD4 was added gene: BRD4 was added to Microcephaly_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: BRD4 was set to Unknown