Clinical Medical College, Ningxia Medical University, No.692 Shengli Street, Xingqing District, Yinchuan, China.
Eye Hospital, School of Optometry and Ophthalmology, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang, 325027, China.
BMC Med Genomics. 2023 Apr 21;16(1):84. doi: 10.1186/s12920-023-01516-9.
Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability, classified into two types RSTS1 (CREBBP-RSTS) and RSTS2 (EP300-RSTS). More often, the clinical features are inconclusive and the diagnosis of RSTS is established in a proband with identification of a heterozygous pathogenic variant in CREBBP or EP300 to confirm the diagnosis.
In this study, to describe an association between the clinical phenotype and the genotype of a RSTS2 patient who was initially diagnosed with severe early-onset high myopia (eoHM) from a healthy Chinese family, we tested the proband of this family by whole exome sequencing (WES) and further verified among other family members by Sanger sequencing. Real-time quantitative PCR was used to detect differences in the relative mRNA expression of candidate genes available in the proband and family members. Comprehensive ophthalmic tests as well as other systemic examinations were also performed on participants with various genotypes.
Whole-exome sequencing revealed that the proband carried the heterozygous frameshift deletion variant c.3714_3715del (p.Leu1239Glyfs3) in the EP300 gene, which was not carried by the normal parents and young sister as verified by Sanger sequencing, indicating that the variant was de novo. Real-time quantitative PCR showed that the mRNA expression of EP300 gene was lower in the proband than in other normal family members, indicating that such a variant caused an effect on gene function at the mRNA expression level. The variant was classified as pathogenic as assessed by the interpretation principles of HGMD sequence variants and ACMG guidelines. According to ACMG guidelines, the heterozygous frameshift deletion variant c.3714_3715del (p.Leu1239Glyfs3) in the EP300 gene was more likely the pathogenic variant of this family with RSTS2.
Therefore, in this paper, we first report de novo heterozygous variation in EP300 causing eoHM-RSTS. Our study extends the genotypic spectrums for EP300-RSTS and better assists physicians in predicting, diagnosis, genetic counseling, eugenics guidance and gene therapy for EP300-RSTS.
Rubinstein-Taybi 综合征（RSTS）的特征为独特的面部特征、宽而常呈角状的拇指和大脚趾、身材矮小以及中度至重度智力残疾，分为 RSTS1（CREBBP-RSTS）和 RSTS2（EP300-RSTS）两种类型。更常见的是，临床特征不明确，RSTS 的诊断是在一个先证者中建立的，该先证者在 CREBBP 或 EP300 中存在杂合致病性变异，以确认诊断。
在这项研究中，为了描述 RSTS2 患者的临床表型与基因型之间的关联，该患者最初被诊断为来自健康中国家庭的严重早发性高度近视（eoHM）。我们对该家系的先证者进行了全外显子组测序（WES）检测，并进一步通过 Sanger 测序在其他家庭成员中进行了验证。实时定量 PCR 用于检测先证者和家庭成员中候选基因的相对 mRNA 表达差异。对具有不同基因型的参与者进行了全面的眼科检查和其他系统检查。
全外显子组测序显示，先证者携带 EP300 基因中的杂合移码缺失变异 c.3714_3715del（p.Leu1239Glyfs3），该变异未被正常父母和年轻妹妹携带，Sanger 测序验证为新生变异。实时定量 PCR 显示，先证者 EP300 基因的 mRNA 表达低于其他正常家庭成员，表明该变异在 mRNA 表达水平上对基因功能产生了影响。根据 HGMD 序列变异和 ACMG 指南的解释原则，该变异被归类为致病性。根据 ACMG 指南，EP300 基因中的杂合移码缺失变异 c.3714_3715del（p.Leu1239Glyfs3）更可能是该 RSTS2 家系的致病变异。
因此，在本文中，我们首次报道了 EP300 导致 eoHM-RSTS 的新生杂合变异。我们的研究扩展了 EP300-RSTS 的基因型谱，更好地帮助医生预测、诊断、遗传咨询、优生学指导和基因治疗 EP300-RSTS。
