CREBBP mutations in individuals without Rubinstein–Taybi syndrome phenotype

Abstract

Mutations in CREBBP cause Rubinstein–Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein–Taybi syndrome. The combined facial signs typical for Rubinstein–Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self‐injurious behavior. Other symptoms were recurrent upper airway infections (n = 5), feeding problems (n = 7) and impaired hearing (n = 7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein–Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein–protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein–Taybi syndrome, and may prove to constitute one (or more) separate entities. © 2016 Wiley Periodicals, Inc.

Genotype–phenotype specificity in Menke–Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP

“…CREBBP encodes a histone acetyl transferase and is a transcriptional activator that interacts with several other transcription factors and proteins (Dutto, Scalera, & Prosperi, ). Overall, the features of these three patients are consistent with the recently described cohort (Table ; Menke et al, , ). Including this article, there are now 25 patients reported in the medical literature without the typical RTS features and exon 30/31 missense CREBBP variants.…”

“…(c) Patient #2 at 7 months of age. Note hypertelorism, broad eyebrows, up‐slanting palpebral fissures, long deep philtrum, large mouth with middle alveolar notch; small chin; low‐set ears; Compare with Patients #9 and #10 reported in Menke et al () and C17, C18, and C19 in Menke et al, who all have the same variant. (d) Patient #3 at 25 months of age.…”

“…Including this article, there are now 25 patients reported in the medical literature without the typical RTS features and exon 30/31 missense CREBBP variants. The functional basis of “exon 30 and 31 missense variant related non‐RTS phenotypes” needs elucidation but Menke et al () hypothesized disturbed protein–protein interactions by altered zinc finger function to be the underlying reason.…”

“…Recently Menke et al () reported 10 distinct de novo missense variants between base pairs 5,128 and 5,614 (NM_004380.2) affecting 9 distinct codons (between codon numbers 1,710 and 1,872) in the 3′ end (last) part of exon 30 or 5′ end (beginning) of exon 31 of CREBBP in 11 patients. The phenotypes of these patients were not (or only to a limited extent) concordant with RTS.…”

Genetics of Short Stature

“…Similarly, the ankyrin repeat domain-containing protein 11 ( ANKRD11 ) interacts with nuclear receptor complexes to modify transcriptional activation and mutations in this gene cause short stature, developmental delay, seizures as well as other features of the KBG syndrome, including macrodontia of the upper central incisors, and skeletal anomalies [52–53]. In addition, heterozygous mutations in transcription coactivators ( CREBBP and EP300 ) cause Rubinstein-Taybi syndrome, characterized by severe short stature, intellectual disability, microcephaly, hearing loss, broad thumbs/halluces, and distinct facial features [54–55]. …”