Divergent variant patterns among 19 patients with Rubinstein-Taybi syndrome uncovered by comprehensive genetic analysis including whole genome sequencing
Divergent variant patterns among 19 patients with Rubinstein-Taybi syndrome uncovered by comprehensive genetic analysis including whole genome sequencing
复制标题
通过包括全基因组测序在内的综合遗传分析发现 19 名 Rubinstein-Taybi 综合征患者的不同变异模式
DOI：
10.1111/cge.14103
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发表时间：
2022
影响因子：
3.5
通讯作者：
Kurosawa K
中科院分区：
文献类型：
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作者：
Enomoto Y;Yokoi T;Tsurusaki Y;Murakami H;Tominaga M;Minatogawa M;Abe-Hatano C;Kuroda Y;Ohashi I;Ida K;Shiiya S;Kumaki T;Naruto T;Mitsui J;Harada N;Kido Y;Kurosawa K
Rubinstein - Taybi综合征（RSTS）的特征是面部畸形、拇指宽阔和智力残疾。CREB结合蛋白（CREBBP）或E1A结合蛋白P300 （EP300）是致病基因。为了阐明与RSTS表型相关的潜在遗传和基因组结构，我们对22名临床诊断的患者进行了针对crebbpand / orep300的全面遗传分析。在11年的研究期间，我们使用了几种分析方法，包括高分辨率熔化、基于阵列的比较基因组杂交、基于面板的外显子组测序、全外显子组测序和全基因组测序（WGS）。我们在19例（86.3%）患者中发现了致病变异，但其变化多端且复杂，必须结合多种分析方法。值得注意的是，我们在两名患者（10.5%,2/19）的非编码区发现了遗传改变：一名患者分散缺失，包括crebbpin的部分5 '‐非翻译区（所有编码外显子都完好无损），另一名患者出现了229‐bp的内含子深度缺失，导致剪接错误。此外，我们还发现了罕见的临床表现：2例ep300变异患者出现神经管发育异常，1例acrebbp变异患者出现肛肠闭锁伴泄殖腔。我们的研究结果扩大了RSTS的等位基因异质性，强调了综合遗传分析的实用性，并表明WGS可能是一种实用的诊断策略。
Rubinstein‐Taybi syndrome (RSTS) is characterized by dysmorphic facial features, broad thumbs, and intellectual disability. CREB‐binding protein (CREBBP) or E1A‐binding protein P300 (EP300) are causative genes. To elucidate the underlying genetic and genomic architecture related to the RSTS phenotype, we performed comprehensive genetic analysis targetingCREBBPand/orEP300in 22 clinically diagnosed patients. During the 11‐year study period, we used several analysis methods including high‐resolution melting, array‐based comparative genomic hybridization, panel‐based exome sequencing, whole exome sequencing, and whole genome sequencing (WGS). We identified the causative variants in 19 patients (86.3%), but they were variable and complex, so we must combine multiple analysis methods. Notably, we found genetic alterations in the non‐coding regions of two patients (10.5%, 2/19): scattered deletions including a partial 5′‐untranslated region ofCREBBPin one patient (all coding exons were intact), and a deep 229‐bp intronic deletion in another patient, resulting in a splicing error. Furthermore, we identified rare clinical findings: two patients with anEP300variant showed abnormal development of the neural tube, and one patient with aCREBBPvariant had anorectal atresia with a cloaca. Our findings expand the allelic heterogeneity of RSTS, underscore the utility of comprehensive genetic analysis, and suggest that WGS may be a practical diagnostic strategy.