ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17473832 Twenty patients with characteristic features of Rubinstein-Taybi syndrome (RSTS) in whom no point mutation in CREBBP or EP300 had been identified in spite of a comprehensive investigation were analysed by quantitative multiplex fluorescent-PCR. Intragenic deletions were identified in 4 patients and an intragenic duplication in one patient. These data were confirmed by array-CGH analysis.
20717166 Reports a male with RSTS resulting from an exon deletion within the CREBBP gene.
18792986 18792986 20689175 30892814 30633342 Additional evidence includes: Bentivegna A et al. (2006) performed mutation analysis in 31 Italian RSTS patients (16 female and 15 males). A total of 5 deletions, 2 of the entire gene (microsatellite segregation analysis proved both affected maternal chromosome) and 3 involving either the 5' or the 3' region in a mosaic condition. The mosaicism was confirm by FISH on buccal smears. Direct sequencing of the rest 26 patients identified 14 de novo mutations: 10 truncating (5 frameshift and 5 nonsense), one splice site, and 3 novel missense mutations, also not present in 100 healthy individuals. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1-170) and will probably destroy a Nuclear Localization Signal. Schorry Ek et al. (2008) describes a cohort of 93 patients meeting diagnostic criteria for Rubinstein-Taybi syndrome (RTS) during 2 international RTS family conferences. Bi-directional sequencing analyses of CREBBP were performed on all 31 coding exons and exon-intron junctions. A total of 64 different variations were observed in the DNA sequence, and determined to be causative variants in 52 patients (52/93=56%), including 10 missense variants and 36 truncating or splice-site variants. The large majority of these variants were novel; only 2 had previously been reported in the literature (c.1651C>A, p.L551I; c.3485A>G, p.N1162S, both at conserved domain). Six large deletions were detected by FISH analysis. Fourteen patients had synonymous changes of unknown significance. No parental samples were available for testing, no functional assays were performed (cases have highly specific phenotypes consistent with what is expected for the gene, but unknown inheritance). Van-Gils J et al., (2019) reported nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. The diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. First fetus had a deletion of the whole CRBBP gene; The second and third fetuses had Intron 21c.3837-2A>Cp.? and Intron 22c.3914+4dupr.(=,3837_3914del) in catalytic core PHD, respectively. The rest of 5 fetuses had deletions in exons: Exon 25c.4274delp.(Asn1425ThrfsTer34)-duplication of the 3?endand flanking region; Exon 14c.2825delp.(Pro942LeufsTer56); Exon 15c.2959C>Tp.(Gln987Ter); Exon5c.1251_1252delp.(His418LeufsTer8); Exon30c.5039_5041delp.(Ser1680del); Exon 30c.5039_5041delp. (Ser1680del). The later two are located in catalytic core HAT domain. No parental studies were reported here.

Haploinsufficiency phenotype comments:

Haploinsufficiency of CREBBP is associated with Rubinstein-Taybi Syndrome (RSTS, OMIM 180849).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Evidence suggests that duplication of the 16p13.3 region including CREBBP results in a distinct clinical phenotype: Thienpont et al. 2010 (PMID: 19833603): Genotype-phenotype study of 12 patients with 16p13.3 duplication. Notably, the authors report a critically duplicated SRO region encompassing a single gene, CREBBP, however, none of the individual cases included only CREBBP. In 10 out of the 12 described probands, the duplication arose de novo. Inheritance of the duplication from a clinically normal parent in two cases indicates that the associated phenotype may be incompletely penetrant. Demeer et al. (2013) (PMID: 23063576): Describes 9 individuals with submicroscopic duplications of 16p13.3 and similar phenotypes: marked speech problems, frequent ocular region involvement with upslanting of the eyes, narrow palpebral fissures, ptosis and strabismus, frequent proximal implantation of thumbs, cleft palate/bifid uvula and inguinal hernia. The smallest duplication in this cohort is 0.24 Mb and encompasses only 2 genes: CREBBP, and the proximally flanking gene TRAP1. The authors note that TRAP1 is only partially duplicated, making the extra-copy "probably not functional". As this patient was said to have the typical clinical features of the 16p13.3 duplication syndrome, the authors felt that these findings corroborated the hypothesis of CREBBP gene overexpression causing most clinical features found in dup16p13.3 patients. The authors also note that this patient (Patient 1) is less severely intellectually disabled, which they suggest may be due to the additional effect of other duplicated genes. See also PMIDs: 23032921, 24035902, etc. Sun M et al., (2014) identified a proband of non-syndromic PRS (Pierre Robin sequence) at age of two months had a duplication of a 11.8 Mb in 16p13.3 [14,999-11,834,999] and a duplication of 3.8 Mb at 14q11.2 [19,694,999-23,534,999](GRCh36/hg18] by aCGH; the derived der(14)t(14;16)(q11.2;p13.13) marker chromosome was confirmed by conventional karyotype and FISH studies. Literature review suggested chromosome 14q11.2 duplication was unlikely to be responsible for the PRS. But 27 cases with pure 16p duplication by CGH were found. 24 of the 28 cases (including this case) had micrognathia, 4 did not. The overlapping duplicated segment in all 28 cases was 163kb in size [chr16:3,701,913-3,864,938]. There were three genes mapped in this region including TRAP1, CREBBP, and ADCY9. The mutant CREBBP gene (OMIM 600140), or microdeletion of chromosome 16p13.3 including the CREBBP gene is responsible for the development of the Rubinstein?Taybi syndrome (OMIM 180849). The mutant DNASE1 gene (OMIM 125505) was susceptible to systemic lupus erythematosus. The significance of TRAP1 (OMIM 606219) was unknown. This study with literature review suggest the duplicated CREBBP gene was associated with incomplete penetrance regarding the mandible development anomalies. Further studies of similar cases are needed to support our findings. 28 cases? Still no case with duplication of CREBBP gene only reported. Though it has been suggested that duplication of CREBBP is the causative gene for this phenotype, to date there has not been a duplication reported that ONLY encompasses CREBBP. Because of this, we have given the CREBBP gene in and of itself a triplosensitivity score of 0.