ClinGen Dosage Sensitivity Curation Page

16p13.3 region (includes CREBBP)

  • Curation Status: Complete
  • id: ISCA-37406
  • Date last evaluated: 2016-06-09
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1

Location Information

Select assembly: (NC_000016.9) ()

Haploinsufficiency phenotype comments:

This region corresponds to the genomic region containing the CREBBP gene. Please see the linked review on the CREBBP gene for documented evidence regarding its haploinsufficiency and Rubinstein-Taybi syndrome.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

This region corresponds to the genomic region containing the CREBBP gene. Please see the linked review for information regarding triplosensitivity of the CREBBP gene, which enumerates evidence relating to focal duplications. Evidence suggests that duplication of a region within 16p13.3 including CREBBP results in a distinct clinical phenotype. These reported duplications are all of variable sizes, and not mediated by segmental duplication. 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 (Please see linked issue for dosage sensitivity scores of the CREBBP gene only). We would like to point out to users that duplications in this area may result in clinical phenotypes, but the exact genomic coordinates of the area are uncertain. Because evidence regarding this duplication is emerging, we have given it a triplosensitivity score of 1. 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. Mattina et al. (2007) (PMID: 23032921) describe a de novo 400-kb duplication including CREBBP and the neighboring ADCY9 gene. This is one of the smallest duplications described in this region. The proband was a 11-year old male with intellectual disability, multiple congenital anomalies, musculoskeletal anomalies, craniofacial dysmorphisms, myopia, microcephaly and growth retardation. Thienpont et al. (2007) (PMID: 17702016) also describe a ~400-kb duplication including CREBBP and parts of the neighboring ADCY9 and TRAP1 genes. This proband exhibited intellectual impairment, atrial septal defect, and mild dysmorphic features. Also see PMIDs 24035902, 18688873, 26873618, etc.