New insights into genetic variant spectrum and genotype–phenotype correlations of Rubinstein‐Taybi syndrome in 39 CREBBP‐positive patients

Abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract Background: Rubinstein-Taybi syndrome (RSTS) is a rare congenital disorder characterized by broad thumbs and halluces, intellectual disability, distinctive facial features, and growth retardation. Clinical manifestations of RSTS are varied and overlap with other syndromes' phenotype, which makes clinical diagnosis challenging. CREBBP is the major causative gene (55%-60% of the cases), whereas pathogenic variants found in EP300 represent the molecular cause in 8% of RSTS patients. A wide range of CREBBP pathogenic variants have been reported so far, including point mutations (30%-50%) and large deletions (10%). Methods: The aim of this study was to characterize the CREBBP genetic variant spectrum in 39 RSTS patients using Multiplex Ligation-dependent Probe Amplification and DNA sequencing techniques (Sanger and Trio-based whole-exome sequencing). Results: We identified 15 intragenic deletions/duplications, ranging from one exon to the entire gene. As a whole, 25 de novo point variants were detected: 4 missense, 12 nonsense, 5 frameshift, and 4 splicing pathogenic variants. Three of them were classified as of uncertain significance and one of the patients carried two different variants. Conclusion: Seventeen of the 40 genetic variants detected were reported for the first time in this work contributing, thus, to expand the molecular knowledge of this complex disorder. K E Y W O R D S CREBBP, epigenetics, genotype-phenotype correlation, Rubinstein-Taybi syndrome 2 of 13 | PÉREZ-GRIJALBA Et AL.

Rubinstein–Taybi syndrome in diverse populations

“…The most common clinical finding in our entire cohort was broad thumbs and/or halluces, angulated or not, present in an average of 97% of individuals. This is consistent with the medical literature (Hennekam, 2006; Pérez‐Grijalba et al, 2019; Schorry et al, 2008). Interestingly, we identified three clinical features that significantly differ across population groups: (a) grimacing smile ( p < .002) and (b) eye abnormalities ( p < .03), which were both observed more frequently in Latin Americans and Asians, and (c) hirsutism ( p < .04) which was seen more frequently in Latin Americans and Middle Easterners.…”

“…Eyes abnormalities included strabismus (8/35), glaucoma (3/35), refraction errors (3/35), nasolacrimal duct obstruction (2/35), cataract (2/35), iris coloboma (1), sclerocornea (1), and hypopigmented retina (1). When excluding intellectual disability, comparison of 21 phenotypic features between our cohort and two previous RSTS studies (Fergelot et al, 2016; Pérez‐Grijalba et al, 2019) showed that the most common features found in both the present study and one of the two previous studies are broad thumbs and halluces. However, we noted some variations in the frequency of clinical features across studies, more manifest between the study by Fergelot et al and our cohort (Table 1).…”

“…The median age was 7 years (age range: 7 months to 47 years), with females representing 63% of the entire cohort (sex ratio: 0.6). (Fergelot et al, 2016;Pérez-Grijalba et al, 2019) showed that the most common features found in both the present study and one of the two previous studies are broad thumbs and halluces. However, we noted some variations in the frequency of clinical features across studies, more manifest between the study by Fergelot et al and our cohort (Table 1).…”

“…A pathogenic variant in CREBBP is identified in 50-60% of all RSTS cases, including deletions of varying sizes in 10% of the affected (Pérez-Grijalba et al, 2019;Schorry et al, 2008). Variants in EP300 are found in a relatively small fraction (8-10%) of RSTS cases, many of them presenting with less marked facial dysmorphism, less severe intellectual disability, and milder skeletal anomalies of thumbs and halluces which are often not angulated (Fergelot et al, 2016;Hamilton et al, 2016).…”

New point mutation in CREBBP Gene cause Rubinstein-Taybi syndrome: A case report

“…RSTS is a rare autosomal dominant inheritance disease with an estimated prevalence of 1:125.000 in live births [2] . The main clinical presentations are congenital multi-system abnormalities such as growth retardation, intellectual disability, microcephaly, broad thumbs and halluces, distinctive facial features, tumor [3][4] . Currently, The diagnosis rate and clinical presentations of RSTS are rare.…”