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.

中文翻译：

---

大型Rubinstein-Taybi队列的筛选确定了许多新颖的变异，并强调了CREBBP组蛋白乙酰转移酶结构域的重要性。

CREBBP和EP300基因内的致病变异占Rubinstein-Taybi综合征（RSTS）的大多数。数据来自针对395例CREBBP进行诊断测试的大型人群，在本研究中被归类为可能致病的19例CREBBP错义变体中，有17例在组蛋白乙酰转移酶（HAT）域内，提供了该域至关重要到CREBBP的正常功能蛋白质（CBP）。此处提供的数据与其他已发表的结果相结合，表明在官方变体解释指南的背景下，CBP HAT域内错义变体的存在可被视为致病性的中等证据。在我们的研究队列中，有129个具有致病性或可能致病性的CREBBP变异体，有5个具有不确定显着性（VUS）变异体，值得进行家族研究。还对剩余的147个先证者进行了EP300筛查，并进一步鉴定出16种致病或可能致病的变异，以及一个VUS。因此，该分析为至少145名患有RSTS的个体提供了分子诊断（37％），并鉴定了多种变异体（n = 133），其中103种是新的。