Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement

Abstract

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Keywords: Genetic Diseases, Inborn; Genetics, Medical; Mental Disorders; Phenotype.

Figure 1

Cardinal features of the clinical diagnostic criteria of face and limbs for Rubinstein-Taybi syndrome (RTS).

Figure 2

Structures and functions of CBP/p300. (A) The proteins CBP and p300 are composed of 2442 amino acids (AA) and 2414 AA, respectively, with 58% of sequence similarity within their domains. The various domains are represented by their position in the AA sequence: N-terminal nuclear receptor interaction domain (NRID or RID), cysteine-histidine rich region 1 (C/H1) containing the transcriptional adapter zinc finger 1 (TAZ1), kinase-inducible domain (KID) interacting domain (KIX), Bromodomain, C/H2 containing a plant homeodomain (PHD), lysine acetyltransferase domain (KAT), C/H3 containing the zinc finger (ZZ) and TAZ2 domains and interferon-binding transactivation domain (IBiD). The Menke-Hennekam syndrome (MKHKS) region corresponds to the location of the missense variants leading to the MKHKS. (B) CBP and p300 act as transcriptional co-activators of target genes by different mechanisms: (1) Binding function by facilitating the physical and functional interactions of TF; (2) scaffolding function allowing the recruitment of TF and in particular CREB; (3) KAT function by catalysing the transfer of acetyl groups on lysine residues of both histone tails and non-histone proteins such as the RNApolII complex and TF. Ac, acetyl group; TBP, TATA binding protein; TF, transcription factors. Adapted from a study by Van Gils et al.

Figure 3

Mutation spectrum of CREBBP and EP300 in individuals with Rubinstein-Taybi syndrome (RTS) (referenced in HGMDPro variant database and/or LOVD). (A) Repartition of 500 pathogenic variants in CREBBP referenced as causing RTS1 including 84 non-sense variants, 192 frameshift variants, 46 splicing variants, 84 missense variants, 75 intragenic deletions, 14 deletions including CREBBP completely, 2 intragenic duplications and 3 complex rearrangements. (B) Repartition of 118 pathogenic variants in EP300 referenced as causing RTS2 including 26 non-sense variants, 56 frameshift variants, 6 splicing variants, 16 missense variants, 11 intragenic deletions and 3 deletions encompassing EP300 completely. Adapted from a study by Van Gils et al.

Figure 4

Molecular diagnostic pathways for Rubinstein-Taybi syndrome. In individuals with clinically classic RTS phenotype, the first-line molecular diagnostic approach is targeted analysis of CREBBP and EP300 by Sanger sequencing and MLPA or by high throughput analysis (aCGH; WES). In individuals in whom RTS is not suspected, aCGH and WES or WGS are performed. ^a Including analysis of CREBBP / EP300 and genes causing related entities; ^b evaluation of results using ACMG classification; ^c episignature specific for RTS ; ^d RNA studies; searches for mosaicism. aCGH, array Comparative Genomic Hybridisation; ACMG, American College of Medical Genetics and Genomics; MLPA, Multiplex Ligation-dependent Probe Amplification; RTS, Rubinstein-Taybi syndrome; WES, whole-exome sequencing; WGS, whole-genome sequencing