Molecular Diagnostic Unit, Fundación Rioja Salud, Logroño, La Rioja, Spain.
Department of Pediatrics, San Pedro Hospital, Logroño, Spain.
BMC Med Genet. 2018 Mar 5;19(1):36. doi: 10.1186/s12881-018-0548-2.
Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in CREBBP and in EP300 genes in 50-60% and 8%, respectively. Up to now, 76 RSTS-EP300 patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying EP300 mutations.
Patients were selected from a cohort of 72 individuals suspected of RSTS after being negative in CREBBP study. MLPA and panel-based NGS EP300 were performed.
Eight patients were found to carry EP300 mutations. Phenotypic characteristics included: intellectual disability (generally mild), postnatal growth retardation, infant feeding problems, psychomotor and language delay and typical facial dysmorphisms (microcephaly, downslanting palpebral fissures, columella below the alae nasi, and prominent nose). Broad thumbs and/or halluces were common, but angulated thumbs were only found in two patients. We identified across the gene novel mutations, including large deletion, frameshift mutations, nonsense, missense and splicing alterations, confirming de novo origin in all but one (the mother, possibly underdiagnosed, has short and broad thumbs and had learning difficulties).
The clinical evaluation of our patients corroborates that clinical features in EP300 are less marked than in CREBBP patients although it is difficult to establish a genotype-phenotype correlation although. It is remarkable that these findings are observed in a RSTS-diagnosed cohort; some patients harbouring EP300 mutations could present a different phenotype. Broadening the knowledge about EP300-RSTS phenotype may contribute to improve the management of patients and the counselling to the families.
Rubinstein-Taybi 综合征（RSTS）是一种罕见的常染色体显性神经发育障碍，其特征为宽拇指和宽足跖。RSTS 由 CREBBP 和 EP300 基因的突变引起，分别占 50-60%和 8%。到目前为止，已经描述了 76 例 RSTS-EP300 患者。我们报告了一组携带 EP300 突变的 RSTS 患者的临床和分子特征。
从 CREBBP 研究阴性的 72 例疑似 RSTS 患者中选择患者。进行 MLPA 和基于面板的 NGS EP300。
发现 8 例患者携带 EP300 突变。表型特征包括：智力障碍（一般为轻度）、出生后生长迟缓、婴儿喂养问题、精神运动和语言发育迟缓以及典型的面部畸形（小头畸形、下斜睑裂、鼻翼低于鼻翼、突出的鼻子）。宽拇指和/或宽足跖很常见，但只有 2 例患者存在拇指弯曲。我们在该基因中发现了新的突变，包括大片段缺失、移码突变、无义突变、错义突变和剪接改变，除 1 例（母亲可能未被诊断，有短而宽的拇指和学习困难）外，均证实为新生突变。
我们患者的临床评估证实，EP300 患者的临床特征比 CREBBP 患者轻，但很难建立基因型-表型相关性。值得注意的是，这些发现是在 RSTS 诊断的患者队列中观察到的；一些携带 EP300 突变的患者可能表现出不同的表型。拓宽对 EP300-RSTS 表型的认识可能有助于改善患者的管理和对家庭的咨询。
