Whole exome sequencing reveals EP300 mutation in mildly affected female: expansion of the spectrum

Abstract

Key Clinical MessageRubinstein–Taybi syndrome is associated with intellectual and physical features. CREBBP and EP300 are causative. Few cases of EP300 mutations are reported. We report a case with mild features of RSTS and EP300 mutation on exome sequencing. This illustrates the utility of exome sequencing to expand every genetic phenotype.

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases

“…Furthermore, inheritance patterns for genes often change with improved knowledge and understanding. It is reasonable to suspect that some of the VUS identified in this study may, in the future, be reclassified as phenotype expansions (Masuda et al, ; Negri et al, ; Sellars, Sullivan, & Schaefer, ). Examples of such variants include the EP300 p.Gln2343Arg variant in patient F (genome 93) and the LMNA p. Arg296Leu variant in patient J (genome 68).…”

“…Furthermore, inheritance patterns for genes often change with improved knowledge and understanding. It is reasonable to suspect that some of the VUS identified in this study may, in the future, be reclassified as phenotype expansions (Masuda et al, 2015;Negri et al, 2015;Sellars, Sullivan, & Schaefer, 2016).…”

Main genetic entities associated with supernumerary teeth

“…30,31 Both genes act as transcriptional coactivators in the expression of genes involved in embryology, cell growth and differentiation, and tumor suppression. They also act as a histone acetyltransferase crucial for gene expression, 30,32 therefore, is regarded as a genetic syndrome caused by altered epigenetic. 33 Approximately 230 causative mutations in CREBBP and 28 in EP300 have been described, accounting for approximately 50 to 70% and 5 to 8% of cases, respectively.…”

Principales entidades genéticas asociadas con dientes supernumerarios

“…30,31 Ambos genes actúan como coactivadores transcripcionales en la expresión de los genes involucrados en la embriología, la proliferación y la diferenciación celular y la supresión tumoral. También actúan como histona acetiltransferasas cruciales para la expresión génica; 30,32 por lo tanto, este se considera un síndrome genético causado por una epigenética alterada. 33 Se describieron aproximadamente 230 mutaciones causales en el gen CREBBP y 28 en el gen EP300, lo que representa aproximadamente del 50 % al 70 % y del 5 % al 8 % de los casos, respectivamente.…”

“…33 Esta entidad afecta a los varones y las mujeres por igual, con una prevalencia de 1 cada 100 000-125 000 nacidos vivos. 31 Se caracteriza por un amplio rango de anomalías congénitas múltiples,como pulgares 30,31 (microcefalia, 32,34 frente prominente, 34 cejas arqueadas, pestañas largas, 34,35 ptosis palpebral, 34 fisuras palpebrales hacia abajo, 30,31,34 pliegue del epicanto, obstrucción del conducto nasolagrimal, estrabismo, 34 tabique nasal ancho, nariz en forma de pico, 30,31,34,35 columela colgante, 30,31 orejas ahuecadas o anguladas en la parte posterior, 36 mohín o sonrisa inusual 30,31,34 y micrognacia). 34,35 El examen intraoral muestra paladar ojival, talón cuspídeo en los incisivos superiores de los dientes permanentes 30,31,34,37,38 en más del 90 % de los casos, 34 lo que resulta en caries, surcos dentales susceptibles e irritación de la lengua durante el habla y la masticación, h i p o d o n c i a , 38 D S r e t e n i d o s 38,39 y d i e n t e s congénitos.…”