Screening of a large Rubinstein–Taybi cohort identified many novel variants and emphasizes the importance of the CREBBP histone acetyltransferase domain

Abstract

Pathogenic variants within the CREBBP and EP300 genes account for the majority of individuals with Rubinstein-Taybi syndrome (RSTS). Data are presented from a large cohort of 395 individuals referred for diagnostic testing of CREBBP, and of the 19 CREBBP missense variants classified as likely pathogenic in this study, 17 were within the histone acetyltransferase (HAT) domain, providing evidence that this domain is critical to the normal function of the CREBBP protein (CBP). The data presented here, combined with other published results, suggest that the presence of a missense variant within the CBP HAT domain can be considered as moderate evidence of pathogenicity in the context of official variant interpretation guidelines. Within our study cohort, 129 had a pathogenic or likely pathogenic CREBBP variant and 5 had a variant of uncertain significance (VUS) which warranted familial studies. 147 of the remaining probands were also screened for EP300 and a further 16 pathogenic or likely pathogenic variants were identified, plus one VUS. Therefore, this analysis has provided a molecular diagnosis in at least 145 individuals with RSTS (37%) and identified a wide range of variants (n = 133) of which 103 were novel.

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

“…The syndrome has been subdivided into type 1 associated with the CREBBP mutation spectrum (RSTS1; OMIM #180849) and type 2 associated with the EP300 mutation spectrum (RSTS2; OMIM #613684). The frequency of abnormalities in the responsible CREBBP gene is approximately 55–75% of cases [ 2 , 12 , 13 , 37 , 65 , 94 , 95 , 96 , 97 , 98 , 99 ]. To date, 500 pathogenic variants in this gene have been referenced as causing RSTS1 (55 of which are unpublished) based on the HGMDPro variant and LOVD databases (analyzed on 27 April 2021) [ 100 , 101 ] ( Tables S1 and S3 ).…”

“…There are no real hot spot mutations in CREBBP with a mutational spectrum distributed along the 31 exons. However, some recurrent mutations have been described and it is noted that about 52% of the reported missense mutations are located in the lysine acetyltranferase (KAT domain) [ 99 ]. An exception to this is the presence of an unstable region of CREBBP located between introns 1 and 2, characterized by a high frequency of repeated or palindromic sequences resulting in recurrent rearrangements in this region [ 37 , 102 , 103 , 104 ].…”

“…Abnormalities in the EP300 gene are responsible for about 8–11% of cases [ 2 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 44 , 99 , 105 , 106 , 107 ]. To date, 118 pathogenic variants in this gene have been referenced as causing RSTS2 (eight of which are unpublished) based on HGMDPro variant and LOVD databases (on 27 April 2021) [ 100 , 101 ] ( Tables S2 and S3 ).…”

“…A correlation between the severity of the phenotype and the presence of large exonic deletions or alterations in function-relevant protein domains or leading to a truncated protein before the KAT domain has been initially suggested [ 38 , 123 , 127 ]. Thanks to recent studies, no significant phenotype/genotype correlation could be shown between the phenotype and the mutation type and location or deletion size for either CREBBP or EP300 genes in RSTS patients [ 17 , 37 , 99 , 104 ].…”

Divergent variant patterns among 19 patients withRubinstein‐Taybisyndrome uncovered by comprehensive genetic analysis including whole genome sequencing

“…Second, it is expected that the diagnostic yield will be improved if WGS is used as the firstline approach for diagnosis, rather than a combination of exome sequencing and array-CGH analyses. Several studies analyzing divergent disease-causing variants in a large cohort recommended direct sequencing, multiplex ligation-dependent probe amplification, and array-CGH analyses of CREBBP and EP300 [23][24][25][26]. However, to the best of our knowledge, no previous study has identified deletions of the5 0 -UTR or deep intron-specific deletions of CREBBP.…”