Alternative titles; symbols
ORPHA: 353281, 783; DO: 1933;
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:1-7,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Chromosome 16p13.3 deletion syndrome | 610543 | 4 |
A number sign (#) is used with this entry because the phenotype is a contiguous gene syndrome caused by deletion of chromosome 16p13.3, affecting the CREBBP (600140), DNASE1 (125505), and TRAP1 (HSP75; 606219) genes.
Rubinstein-Taybi syndrome-1 (RSTS1; 180849) is caused by point mutations or deletions within the CREBBP gene.
Bartsch et al. (1999) reported 2 patients with RSTS caused by large deletions of chromosome 16p13.3 who died in infancy, which is rare in RSTS. One of these patients had accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, and renal agenesis. The other patient had severe neonatal seizures. The combination of RSTS and hypoplastic left heart had previously been described in only 1 patient (Stevens and Bhakta, 1995). Bartsch et al. (1999) suggested that patients with severe RSTS and large deletions had a distinct contiguous gene syndrome.
Bartsch et al. (2006) provided further analysis of the 2 patients with severe RSTS reported by Bartsch et al. (1999) and a third patient reported by Bartsch et al. (2002). All had a severe phenotype with failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectively). Bartsch et al. (2006) noted that Kimura et al. (1993) had described a Japanese boy with RSTS and features of DiGeorge syndrome (188400) who died at age 20 months.
Using FISH studies in 3 patients with severe RSTS who died in infancy, Bartsch et al. (2006) identified deletions of chromosome 16p13.3 ranging from 400 kb to over 3 Mb. The deletions in all 3 patients included the entire CREBBP gene as well as 3-prime distal flanking regions containing the DNASE1 and TRAP1 genes. Bartsch et al. (2006) suggested that 'severe RSTS' is distinct from RSTS and represents a contiguous gene syndrome. The authors suggested that the size of the deletion interval should be determined in such patients because of the risk of critical infections and high mortality.
Stef et al. (2007) reported 2 patients with typical RSTS who were found by gene dosage studies to have a large deletion of the chromosome 16p13 region, including the CREBBP and DNASE1 genes. Although the patients had a severe form of RSTS, neither had a particularly severe form of mental retardation, and neither was prone to infection. Stef et al. (2007) concluded that the presentation of these 2 patients did not confirm the phenotype described by Bartsch et al. (2006).
Gervasini et al. (2007) used FISH and microsatellite analysis to screen 42 Italian RSTS patients and identified deletions involving the CREBBP gene that ranged in size from 150 kb to 2.6 Mb in 6 patients. Three of the patients were low-level mosaics, with the deletion present in less than 30% of lymphocytes and in less than 20% of epithelial cells analyzed. The authors stated that the clinical presentation was typical in all cases, but more severe in the 3 patients with constitutional deletions, and suggested that there may be underdiagnosis of a few cases of mild RSTS.
Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (see also 613458), and 22q11.2 (192430, 608363). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. Sahoo et al. (2011) identified a 16p13.11 microdeletion in 32 individuals; 3 were de novo, 5 maternally inherited, 6 paternally inherited, and 18 of unknown inheritance. The average age at diagnosis was 6.6 years, with an age range of 0.5 to 30 years, and the indications for study included developmental delay, autism spectrum disorder, dysmorphic features, multiple congenital anomalies, epilepsy, and seizure disorder. The microdeletion was seen in 32 of 23,250 cases referred to their laboratory for a frequency of 0.14%, compared with 0 of 5,674 controls (Itsara et al., 2009), p = 0.0101. The frequency of this microdeletion in a schizophrenia population was reported as 0.12% versus 0.04% in controls (Ingason et al., 2011). This deletion was seen in 0.48% of cases in a neurodevelopmental deficit population and in 0.0% of controls in the study reported by Vassos et al. (2010). Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and implied the existence of shared biologic pathways among multiple neurodevelopmental conditions.
Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 16p13.11 deletion was identified in 22 cases and 3 controls for a p value of 0.0063 and an overall frequency of 1 in 716 cases.
Using a combination of FISH and multiple ligation-dependent probe amplification (MLPA) analysis, Rusconi et al. (2015) identified 14 different and novel CREBBP deletions in 14 of 171 patients with a clinical diagnosis of RSTS. The deletions, which accounted for 23% of detected CREBBP mutations in this cohort, ranged in size from 930 bp encompassing single exons to 1.35 Mb encompassing the whole gene and neighboring genes. Genotype/phenotype correlations indicated that patients with larger deletions did not always have a more severe phenotype than those with smaller deletions or point mutations, suggesting that the idea of a contiguous gene deletion syndrome in such patients, as proposed by Bartsch et al. (2006), may not be accurate.
Bartsch, O., Locher, K., Meinecke, P., Kress, W., Seemanova, E., Wagner, A., Ostermann, K., Rodel, G. Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. J. Med. Genet. 39: 496-501, 2002. [PubMed: 12114483] [Full Text: https://doi.org/10.1136/jmg.39.7.496]
Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M. Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome. Hum. Genet. 120: 179-186, 2006. [PubMed: 16783566] [Full Text: https://doi.org/10.1007/s00439-006-0215-0]
Bartsch, O., Wagner, A., Hinkel, G. K., Krebs, P., Stumm, M., Schmalenberger, B., Bohm, S., Balci, S., Majewski, F. FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy. Europ. J. Hum. Genet. 7: 748-756, 1999. [PubMed: 10573006] [Full Text: https://doi.org/10.1038/sj.ejhg.5200378]
Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovannucci-Uzielli, M. L., Pessagno, A., Lucci-Cordisco, E., Pinto, A. M., Salviati, L., Selicorni, A., Tenconi, R., Neri, G., Larizza, L. High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints. Genomics 90: 567-573, 2007. [PubMed: 17855048] [Full Text: https://doi.org/10.1016/j.ygeno.2007.07.012]
Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O. P. H., Buizer-Voskamp, J. E., Strengman, E., Francks, C., Muglia, P., Gylfason, A., Gustafsson, O., and 37 others. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Molec. Psychiat. 16: 17-25, 2011. [PubMed: 19786961] [Full Text: https://doi.org/10.1038/mp.2009.101]
Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R. M., Myers, R. M., Ridker, P. M., Chasman, D. I., Mefford, H., Ying, P., Nickerson, D. A., Eichler, E. E. Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84: 148-161, 2009. [PubMed: 19166990] [Full Text: https://doi.org/10.1016/j.ajhg.2008.12.014]
Kaminsky, E. B., Kaul, V., Paschall, J., Church, D. M., Bunke, B., Kunig, D., Moreno-De-Luca, D., Moreno-De-Luca, A., Mulle, J. G., Warren, S. T., Richard, G., Compton, J. G., and 22 others. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet. Med. 13: 777-784, 2011. [PubMed: 21844811] [Full Text: https://doi.org/10.1097/GIM.0b013e31822c79f9]
Kimura, H., Ito, Y., Koda, Y., Hase, Y. Rubinstein-Taybi syndrome with thymic hypoplasia. Am. J. Med. Genet. 46: 293-296, 1993. [PubMed: 8488874] [Full Text: https://doi.org/10.1002/ajmg.1320460311]
Rusconi, D., Negri, G., Colapietro, P., Picinelli, C., Milani, D., Spena, S., Magnani, C., Silengo, M. C., Sorasio, L., Curtisova, V., Cavaliere, M. L., Prontera, P., and 11 others. Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire. Hum. Genet. 134: 613-626, 2015. [PubMed: 25805166] [Full Text: https://doi.org/10.1007/s00439-015-1542-9]
Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., Torchia, B. S., Neill, N., Casci, I., Bejjani, B. A., Shaffer, L. G. Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genet. Med. 13: 868-880, 2011. [PubMed: 21792059] [Full Text: https://doi.org/10.1097/GIM.0b013e3182217a06]
Stef, M., Simon, D., Mardirossian, B., Delrue, M.-A., Burgelin, I., Hubert, C., Marche, M., Bonnet, F., Gorry, P., Longy, M., Lacombe, D., Coupry, I., Arveiler, B. Spectrum of CREBBP gene dosage anomalies in Rubinstein-Taybi syndrome patients. Europ. J. Hum. Genet. 15: 843-847, 2007. [PubMed: 17473832] [Full Text: https://doi.org/10.1038/sj.ejhg.5201847]
Stevens, C. A., Bhakta, M. G. Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am. J. Med. Genet. 59: 346-348, 1995. [PubMed: 8599359] [Full Text: https://doi.org/10.1002/ajmg.1320590313]
Vassos, E., Collier, D. A., Holden, S., Patch, C., Rujescu, D., St Clair, D., Lewis, C. M. Penetrance for copy number variants associated with schizophrenia. Hum. Molec. Genet. 19: 3477-3481, 2010. [PubMed: 20587603] [Full Text: https://doi.org/10.1093/hmg/ddq259]