Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
J Med Genet. 2021 Mar;58(3):178-184. doi: 10.1136/jmedgenet-2019-106498. Epub 2020 May 19.
Beckwith-Wiedemann Syndrome (BWS) is characterised by overgrowth and tumour predisposition. While multiple epigenetic and genetic mechanisms cause BWS, the majority are caused by methylation defects in imprinting control regions on chromosome 11p15.5. Disease-causing methylation defects are often mosaic within affected individuals. Phenotypic variability among individuals with chromosome 11p15.5 defects and tissue mosaicism led to the definition of the Beckwith-Wiedemann Spectrum (BWSp). Molecular diagnosis of BWSp requires use of multiple sensitive diagnostic techniques to reliably detect low-level aberrations.
Multimodal BWS diagnostic testing was performed on samples from 1057 individuals. Testing included use of a sensitive qRT-PCR-based quantitation method enabling identification of low-level mosaic disease, identification of CNVs within 11p15.5 via array comparative genomic hybridisation or qRT-PCR, and Sanger sequencing of .
A molecular diagnosis was confirmed for 27.4% of individuals tested, of whom 43.4% had mosaic disease. The presence of a single cardinal feature was associated with a molecular diagnosis of BWSp in 20% of cases. Additionally, significant differences in the prevalence of mosaic disease among BWS molecular subtypes were identified. Finally, the diagnostic yield obtained by testing solid tissue samples from individuals with negative blood testing results shows improved molecular diagnosis.
This study highlights the prevalence of mosaic disease among individuals with BWSp and the increases in diagnostic yield obtained via testing both blood and solid tissue samples from affected individuals. Additionally, the results establish the presence of a molecular diagnosis in individuals with very subtle features of BWSp.
贝克威思-威德曼综合征（BWS）的特征是过度生长和肿瘤易感性。虽然多种表观遗传和遗传机制导致 BWS，但大多数是由于 11p15.5 染色体上的印迹控制区的甲基化缺陷引起的。致病的甲基化缺陷在受影响的个体中通常是镶嵌的。11p15.5 缺陷个体之间的表型变异性和组织镶嵌性导致了贝克威思-威德曼谱（BWSp）的定义。BWSp 的分子诊断需要使用多种敏感的诊断技术来可靠地检测低水平的异常。
对 1057 名个体的样本进行了多模态 BWS 诊断测试。测试包括使用一种敏感的基于 qRT-PCR 的定量方法来识别低水平的镶嵌疾病，通过阵列比较基因组杂交或 qRT-PCR 鉴定 11p15.5 内的 CNV，并对. 进行 Sanger 测序。
对 27.4%的受检个体进行了分子诊断，其中 43.4%的个体患有镶嵌疾病。20%的病例中，单一主要特征的存在与 BWSp 的分子诊断相关。此外，还确定了 BWS 分子亚型中镶嵌疾病的患病率存在显著差异。最后，对血液检测结果为阴性的个体的实体组织样本进行检测，提高了分子诊断的检出率。
本研究强调了 BWSp 个体中镶嵌疾病的普遍性，以及通过对受影响个体的血液和实体组织样本进行检测，诊断率的提高。此外，研究结果还证实了在具有非常微妙的 BWSp 特征的个体中存在分子诊断。
