DO: 0060970;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.12 | Cornelia de Lange syndrome 6 | 620568 | Autosomal dominant | 3 | BRD4 | 608749 |
A number sign (#) is used with this entry because of evidence that Cornelia de Lange syndrome-6 (CDLS6) is caused by heterozygous mutation in the BRD4 gene (608749) on chromosome 19p13.
Cornelia de Lange syndrome (CDLS) is a genetically 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 60% of patients have mutations in the NIPBL gene (608667) (summary by Musio et al., 2006 and Hoppman-Chaney et al., 2012).
For a general phenotypic description and a discussion of genetic heterogeneity of Cornelia de Lange syndrome, see CDLS1 (122470).
Olley et al. (2018) reported 4 unrelated patients with microcephaly, developmental delay, impaired intellectual development (ID), and dysmorphic facial features including synophrys, arched eyebrows, short nose, and long philtrum. One patient had a typical facial appearance of CDLS, 2 patients were classified as having atypical CDLS based on facial features, and 1 patient had developmental delay, ventricular septal defect, cleft lip, and hypertelorism, but was not suspected of having CDLS. All 4 patients had a mutation in the BRD4 gene.
Jouret et al. (2022) described 12 patients, ranging in age from 10 weeks to 32 years, and 2 prenatal cases with microcephaly, intrauterine growth restriction, and other features. Microcephaly was present in 12 of the 14 patients. Initial global developmental delay was seen in 12 patients. Impaired intellectual development was identified in 5 of 11 patients over the age of 3 years, 4 of 11 had learning difficulties without impaired ID, and 2 had an IQ within the normal range without learning difficulties. Five of 11 patients had psychiatric disorders, including psychotic disorder, schizophrenia, obsessive compulsive disorder, poor performance in socialization, and other conditions. A recognizable pattern of facial features, including arched eyebrows, sometimes with synophrys, frontal upsweep of hair, prominent incisors, and short nose with anteverted nostrils, was seen in 6 of 7 patients. The authors noted that the phenotype evolved with age and that none of the patients had a classic CDLS phenotype because none had growth failure, hypertrichosis, or radial and limb anomalies. All of the patients had a mutation in the BRD4 gene.
The heterozygous mutations in the BRD4 gene that were identified in patients with CDLS6 by Olley et al. (2018) and Jouret et al. (2022) occurred de novo.
Among 92 patients with features of Cornelia de Lange syndrome who were negative for mutations in known causative genes, Olley et al. (2018) identified 2 unrelated patients with de novo heterozygous mutations in the BRD4 gene: a missense mutation (Y430C; 608749.0001) and a 1.04-Mb deletion that included BRD4 and 28 other protein-coding genes. In 2 additional patients, who were not part of the original cohort, the authors identified de novo heterozygous frameshift mutations in BRD4 (see, e.g., 608749.0002). The authors then reviewed phenotypes of other patients with heterozygous multigenic deletions encompassing BRD4 and recognized a significant overlap with the CDLS phenotype, suggesting that BRD4 haploinsufficiency is the likely cause of CDLS6. The authors showed that the BRD4 missense variant resulted in more typical CDLS; this variant retained the ability to coimmunoprecipitate with NIPBL (608667), the gene that is mutated in CDLS1 (122470), but had decreased binding to acetylated histones of promoter and superenhancer genes. Functional analyses showed that BRD4 and NIPBL correlated binding at superenhancer genes and appeared to coregulate developmental gene expression.
Through an international collaboration, Jouret et al. (2022) identified 14 patients, including 2 fetuses and 12 patients aged 10 weeks to 32 years, with mutations involving the BRD4 gene. The mutations included 8 point mutations and 6 large deletions. Among the point variants, 4 were truncating (see, e.g., 608749.0002-608749.0003) and 4 were missense (see, e.g., 608749.0001, 608749.0004). Deletion size varied from 46 kb to 2.2 Mb; the 46 kb deletion overlapped only the BRD4 gene. Although some of the patients had microcephaly, arched eyebrows, synophrys, short nose, and anteverted nostrils, the authors thought that none of the 14 patients had a classic CDLS phenotype because none had growth failure, hypertrichosis, or radial/limb anomalies.
Hoppman-Chaney, N., Jang, J. S., Jen, J., Babovic-Vuksanovic, D., Hodge, J. C. In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange syndrome. Am. J. Med. Genet. 158A: 193-198, 2012. [PubMed: 22106055] [Full Text: https://doi.org/10.1002/ajmg.a.34360]
Jouret, G., Heide, S., Sorlin, A., Faivre, L., Chantot-Bastaraud, S., Beneteau, C., Denis-Musquer, M., Turnpenny, P. D., Coutton, C., Vieville, G., Thevenon, J., Larson, A., and 27 others. Understanding the new BRD4-related syndrome: clinical and genomic delineation with an international cohort study. Clin. Genet. 102: 117-122, 2022. [PubMed: 35470444] [Full Text: https://doi.org/10.1111/cge.14141]
Musio, A., Selicorni, A., Focarelli, M. L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P., Larizza, L. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nature Genet. 38: 528-530, 2006. [PubMed: 16604071] [Full Text: https://doi.org/10.1038/ng1779]
Olley, G., Ansari, M., Bengani, H., Grimes, G. R., Rhodes, J., von Kriegsheim, A., Blatnik, A., Stewart, F. J., Wakeling, E., Carroll, N., Ross, A., Park, S. M., Deciphering Developmental Disorders Study, Bickmore, W. A., Pradeepa, M. M., FitzPatrick, D. R. BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome. Nature Genet. 50: 329-332, 2018. Note: Erratum: Nature Genet 50: 767, 2018; Erratum: Nature Genet. 51: 1192, 2019. [PubMed: 29379197] [Full Text: https://doi.org/10.1038/s41588-018-0042-y]