Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein-Taybi syndrome detected by aCGH

Abstract

We demonstrate the utility of an exon coverage microarray platform in detecting intragenic deletions: one in exons 24-27 of the EP300 gene and another in exons 27 and 28 of the CREBBP gene in two patients with Rubinstein-Taybi syndrome (RSTS). RSTS is a heterogeneous disorder in which approximately 45-55% of cases result from deletion or mutations in the CREBBP gene and an unknown portion of cases result from gene changes in EP300. The first case is a 3-year-old female with an exonic deletion of the EP300 gene who has classic facial features of RSTS without the thumb and great toe anomalies, consistent with the milder skeletal phenotype that has been described in other RSTS cases with EP300 mutations. In addition, the mother of this patient also had preeclampsia during pregnancy, which has been infrequently reported. The second case is a newborn male who has the classical features of RSTS. Our results illustrate that exon-targeted array comparative genomic hybridization (aCGH) is a powerful tool for detecting clinically significant intragenic rearrangements that would be otherwise missed by aCGH platforms lacking sufficient exonic coverage or sequencing of the gene of interest.

Figure 1

Clinical photos of the patients. (a) Case 1: Dysmorphic facial features include hypotelorism, deep-set eyes with luxuriant eyelashes, bushy eyebrows, synophrys, hirsutism, prominent nasal tip, cupid-bow-shaped/beaked upper lip and high-arched palate. (b) Case 2: Facial features of case 2 include hirsutism, low hairlines, glabellar nevus flammeus, ptosis, epicanthal folds, downslanting palpebral fissures, nasal septum below alae nasi and microstomia. Thumbs are broad and angulated; palmar creases are deep and simple. Halluces are broad but not angulated. Persistent fetal pads were noted on all fingers.

Figure 2

(a) Profile of the microarray analysis showing the deleted region as indicated in the red circle (the gain on chromosome 21 as shown in green dots is also present in the mother (data not shown)). (b) Each of the oligos (red square) in the deleted region is displayed in the UCSC genome browser (build HG 18) corresponding to the four deleted exons of the EP300 gene (exons 24–27). (c) The MLPA profile demonstrating the deletion of exons 24–27 of the EP300 gene as indicated by the arrow with the number for each exon.

Figure 3

(a) Profile of the microarray analysis showing the deleted region as indicated in the red circle (the gain on Xp as shown in green dots is also present in the mother (data not shown), whereas the yellow dot on chromosome 10 represent a highly polymorphic region, which is also present in the Toronto database). (b) The deleted oligos displayed in the UCSC genome browser (build HG 18) corresponding to exons 27 and 28 of the CREBBP gene. (c) The MLPA profile demonstrating the two deleted exons of the CREBBP gene (exons 27–28) as indicated by the arrow with the number for each exon.