Microcephaly

Gene: BRD4

Green List (high evidence)

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

• 29379197
• 30302754
• 11997514
• 34035299

I don't know

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 BRD4

Created: 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

• 29379197
• 30302754