Expanding the phenotypic spectrum in EP300‐related Rubinstein–Taybi syndrome

Abstract

Rubinstein-Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research-based whole-genome sequencing of the family trio. The child's presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by "hypothesis free" methods, including microarray, exome, and whole-genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300-related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods.

Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch

“…In addition, our finding of the p300 function in OL fate specification has an implication on the pathogenesis of Rubinstein-Taybi syndrome. A type 2 form of the disease caused by a loss-of-function mutation in EP300 (p300) manifests, along with other systemic abnormalities, hypoplasia of the corpus callosum, reflecting congenital hypomyelination (Solomon et al, 2015). Given this critical role for Hdac3/p300 as a proximal regulator of the OL-astrocyte fate switch, it is conceivable that enhancing Hdac3/p300 interaction or activity might promote or maintain OL identity, while reprogramming astrocytes for OL regeneration.…”

First case report of inherited Rubinstein-Taybi syndrome associated with a novel EP300 variant

“…To date, 246 disease causing mutations in the CREBBP gene have been reported to cause RSTS [7]. In contrast, only 23 RSTS patients with EP300 mutations, and a total of 34 mutations, have been described in this gene [10, 14]. The mutations described in both range from point mutations to whole gene deletions and chromosome rearrangements, and spread across the entire length of the genes.…”

Diagnosis of D-Bifunctional Protein Deficiency through Whole-Genome Sequencing: Implications for Cost-Effective Care

“…In addition to the presence of a possible genetic/genomic but molecularly undiagnosed disorder, further inclusion/exclusion criteria for the research study are summarized as follows: the proband must be the biological offspring of the parents (cases of nonparentage ascertained through WGS are 'silently' dropped from analysis); parents must be at least 18 years of age; there must be no parental history of cancer in the last 5 years, so that mutations that may be related to cancer or treatment will not affect analyses, and both parents must be willing to enroll in the research study to allow trio-based WGS and related investigations. Other relatives may also participate and typically undergo WGS concurrently with the primary trio Solomon et al, 2015].…”

“…For further details on methods, see our publications describing WGS to elucidate the causes of congenital disorders Stittrich et al, 2014;Solomon et al, 2015].…”