Rubinstein-Taybi syndrome is a rare genetic disorder characterized by postnatal growth retardation, moderate to severe mental retardation (ID), and multiple characteristic malformations. Despite its prominent facial features, broad thumbs and hallux, the diagnosis of RSTS is sometimes challenging due to the high variability of phenotypes and genotypes [39]. Whole exome sequencing (WES) is a reliable and rapid diagnostic tool for suspected genetic diseases and has been strongly applied in medical practice [19].
In this study, we report the deletion of exon 27 to exon 30 of the CREBBP gene and the 3’ adjacent genes, TRAP1, in one patient molecularly confirming the diagnosis of RSTS. To best of our knowledge, this mutation has not been published previously. We described the patient’s clinical manifestations in detail, and found that in addition to the typical systemic manifestations of the syndrome, such as intellectual disability and facial dysmorphism, the outstanding manifestation of the child was ocular abnormalities (infantile glaucoma, ptosis and epicanthus) and significantly lower IQ (10–20). The child’s IQ was significantly lower than most other reports (average IQ was reported between 35 and 50) [40], who can only understand simple, daily sentences and single words, has no language or only a few words, and usually walks unsteadily. Since no observable genotype-phenotype relationship has been observed for other mutations in RSTS, this mutation is less likely to lead to a specific clinical RSTS subtype, although this cannot be completely ruled out.
The reported CREBBP deletions were spread along the gene ranging in size from one exon to the entire gene (Table 1). Half of the patients carried deletions of five exons or more [26]. Although not confirmed in other populations [28], the association between severe phenotypes and deletion of CREBBP and adjacent genes has been reported [25]. In addition, researchers did not find an association of larger deletions with disease severity [26, 41]. No correlation was observed between the location of the affected exons and the phenotype [26, 27]. However, previous studies have reported a worse cognitive phenotype in patient carriers of mutations that affect the CREBBP histone acetyltransferase (HAT) domain [28], which also seen in our case. CREBBP is highly conserved, with 95% homology between the human and murine genes [42]. The reported mutational spectrum of CREBBP, including deletions, point mutations, and large rearrangements, distributed throughout the 31 coding exons. However, the highly conserved HAT region is believed to be particularly important for the RSTS phenotype. A large study including 93 patients with RSTS found that almost all the truncating mutations lead to premature termination of the protein before or within the HAT domain (corresponding to exons 19–30) and there was a clustering of single amino acid changes in the HAT region, indicating the importance of HAT activity in the phenotype [14, 38]. In this patient, three exons (exons 27–30) of CREBBP are deleted. This is predicted to disrupt HAT activity and supports the importance of the HAT domain in causing the phenotype of RSTS.
Table 1
CREBBP deletions reported in previous studies
No.
|
CREBBP deletion
|
Databases (Decipher, public HGMD, LOVD) and references
|
1
|
Ex1del
|
HGMD (Breuning et al., 1993 [33])
|
2
|
Ex2del
|
LOVD (Breuning et al., 1993 [33])
|
3
|
Ex1-2del
|
LOVD (Breuning et al., 1993 [33])
|
4
|
Ex1-3del
|
Choi et al., 2021 [32]
|
5
|
Ex1-19del
|
Roelfsema et al., 2005 [29]
|
6
|
Ex1-31del
|
LOVD (Mogensen et al., 2011[34]; Bentivegna et al., 2006 [35])
|
7
|
Ex2-3del
|
Cross et al., 2020 [27]
|
8
|
Ex3-31del
|
Pérez-Grijalba et al., 2019 [26]
|
9
|
Ex4-16del
|
HGMD (Bentivegna et al., 2006 [35], Rusconi et al., 2015 [28])
|
10
|
Ex6-13del
|
Cross et al., 2020 [27]
|
11
|
Ex6-31del
|
HGMD (Rusconi et al., 2015 [28], Choi et al., 2021 [32])
|
12
|
Ex7-8del
|
Cross et al., 2020 [27]
|
13
|
Ex9-14del
|
Cross et al., 2020 [27]
|
14
|
Ex12-31del
|
Rusconi et al., 2015 [28]
|
15
|
Ex17-28del
|
Cross et al., 2020 [27]
|
16
|
Ex17-31del
|
HGMD (López et al. 2018 [36] Choi et al., 2021 [32],)
|
17
|
Ex20-31del
|
Elalaoui SC, et al., 2021 [37]
|
18
|
Ex21del
|
Pérez-Grijalba et al., 2019 [26]
|
19
|
Ex22-23del
|
HGMD (Bentivegna et al., 2006 [35])
|
20
|
Ex24-28del
|
Cross et al., 2020 [27]
|
21
|
Ex24-31del
|
Pérez-Grijalba et al., 2019 [26]
|
22
|
Ex26-30del
|
Pérez-Grijalba et al., 2019 [26]
|
23
|
Ex27-28del
|
Cross et al., 2020 [27]
|
24
|
Ex27-29del
|
Cross et al., 2020 [27]
|
25
|
Ex27-30del
|
This study
|
26
|
Ex29-30del
|
Pérez-Grijalba et al., 2019 [26]
|
27
|
Ex29-31del TRAP1
|
Lai et al., 2012 [38], Rusconi et al.,2015 [28]
|
28
|
Ex31del
|
HGMD (Bentivegna et al., 2006 [35], Rusconi et al., 2015 [28])
|
In our patient, another affected gene was the TRAP1 gene encoding tumor necrosis factor receptor-associated protein 1. As a mitochondrial ATP-binding protein, TRAP1 gene participants in maintaining mitochondrial function [43]. TRAP1 also acts as a molecular chaperone and is a heat shock protein 90-related protein [44]. We speculated that the more severe phenotype in this patient may also be related to partial deletion of TRAP1 gene.
In addition, deletion of HAT domain of CREBBP has been reported to causing ocular abnormality [7, 26]. Various ocular features have been reported in RSTS, including lacrimal duct obstruction, corneal abnormalities, cataracts, congenital glaucoma, colobomas, and retinal abnormalities with an abnormal VEP [45, 46]. Therefore, the presence of childhood glaucoma in the present patients corresponds to the ocular spectrum of RSTS. Brei and colleagues found 32 glaucoma and 25 corneal opacities in 614 patients with RSTS, and they concluded that the incidence of glaucoma in RSTS exceeds that of the general population and is often congenital or develops in infancy [47]. Since congenital glaucoma is a preventable cause of blindness and early treatment is critical, it is especially important to request a detailed ophthalmological examination to rule out ocular complications after diagnosis [40]. It is recommended that all children with RSTS should undergo a detailed ophthalmologic examination by a pediatric ophthalmologist shortly after diagnosis, or at 6 months of age in patients with RSTS diagnosed in the neonatal period. If an eye problem is suspected, referral to an ophthalmologist should be made as soon as possible. Depending on the examination results, regular ophthalmological visits should be performed every 12 months or less [48].
Although whole exome sequencing has the advantage of high efficiency and convenience in screening pathogenic genes, the importance of traditional sanger sequencing cannot be ignored. For example, in our research, we find a large deletion mutation of exon 29 to 31 on CREBBP gene, after verification by Sanger sequencing, it was finally confirmed to be the mutation covers the exon 1 region and part of the intron 1 region of the TRAP1 gene, and the entire region from intron 27 to exon 30 of the CREBBP gene.
In conclusion, the genetic variant found in this case was reported in this work for the first time, hence, contributing to the RSTS molecular knowledge and expanding the CREBBP genetic variant repertoire of this complex disorder. Meanwhile, this study further suggests the importance of ophthalmic examination and follow-up in patients with RSTS. Timely and correct treatment for congenital glaucoma and other ophthalmic diseases is helpful to improve the quality of life of children.