Insights into genotype–phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein–Taybi syndrome patients

Abstract

The genetic basis of Rubinstein-Taybi syndrome (RSTS), a rare, sporadic, clinically heterogeneous disorder characterized by cognitive impairment and a wide spectrum of multiple congenital anomalies, is primarily due to private mutations in CREBBP (approximately 55% of cases) or EP300 (approximately 8% of cases). Herein, we report the clinical and the genetic data taken from a cohort of 46 RSTS patients, all carriers of CREBBP point mutations. Molecular analysis revealed 45 different gene alterations including 31 inactivating (21 frameshift and 10 nonsense), 10 missense and 4 splicing mutations. Bioinformatic tools and transcript analyses were used to predict the functional effects of missense and splicing alterations. Of the 45 mutations, 42 are unreported and 3 were described previously. Recurrent mutations maybe a key tool in addressing genotype-phenotype correlations in patients sharing the same defects (at the genomic or transcript level) and specific clinical signs, demonstrated here in two cases. The clinical data of our cohort evidenced frequent signs such as arched eyebrows, epicanthus, synophrys and/or frontal hypertrichosis and broad phalanges that, previously overlooked in RSTS diagnosis, now could be considered. Some suggested correlations between organ-specific anomalies and affected CREB-binding protein domains broaden the RSTS clinical spectrum and perhaps will enhance patient follow-up and clinical care.

Clinical exome sequencing identifies novel CREBBP variants in 18 Chinese Rubinstein–Taybi Syndrome kids with high frequency of polydactyly

“…In addition, potential disease‐causing CNVs can be identified from NGS data except for the SNV findings, and 37% (7/19) of deletions involved CREBBP gene from CES were detected. In the reported point variants of CREBBP gene, missense variants account for 17%–22% (Lee et al, ; Spena, Milani, et al, ). However, we found a lower incidence (2%; 2/12) of missense variants of point variants, which reinforces the previous hypothesis that missense variants may account for a very low proportion of RSTS cause (Lee et al, ).…”

“…Spena et al also reported eight of 21 frameshift variations clustered in this region (Spena, Milani, et al, ). Hence, this region, especially base pairs 5,837 which have related four frameshift variants involved four RSTS patients (Rokunohe, Nakano, Akasaka, Toyomaki, & Sawamura, ; Spena, Milani, et al, ), may be a “hot spot” for frameshift and nonsense variants in RSTS patients. Another region locates in exon 2 at the 5′ end of the CREBBP .…”

“…In addition, neither the parents nor the healthy brother, carry this variant in hematologic cells. This frameshift variant has been reported in a 5‐year‐old Italian girl with RSTS and anomalies of kidney and ureters, with heterozygotes (Spena, Milani, et al, ). Different from the reported case, our patient had bilateral cutaneous syndactyly of the second to fourth digits in hands and of 1/2 toes in feet.…”

Progress in pediatrics in 2015: choices in allergy, endocrinology, gastroenterology, genetics, haematology, infectious diseases, neonatology, nephrology, neurology, nutrition, oncology and pulmonology

“…Little is known about genotype-phenotype correlations in RSTS. Recurrent mutations maybe a key tool in addressing genotype-phenotype correlations in patients sharing the same defects and specific clinical signs, as demonstrated in two cases in a clinical cohort of 46 RSTS patients [48]. Nevertheless, a severe phenotype has been reported in RSTS patients who show large gene deletions.…”

Hepatoblastoma in Rubinstein-Taybi Syndrome: A Case Report

“…Moreover, intellectual disability and major malformations are among the features of this syndrome . Mutations in the genes CREBBP and EP300 are present in 55–60% of patients …”