Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
Center of Excellence "TeleOrto" for Telediagnostics and Treatment of Disorders and Injuries of the Locomotor System, Department of Medical Informatics and Telemedicine, Medical University of Warsaw, Warsaw, Poland.
Am J Med Genet A. 2022 May;188(5):1482-1487. doi: 10.1002/ajmg.a.62670. Epub 2022 Feb 2.
Genetic mosaicism caused by postzygotic mutations is of a great interest due to its role in human disease. Monozygotic twins arising from a single zygote are considered as genetically identical, and any differences likely to be caused by postzygotic events. Thus, phenotypically discordant monozygotic twins offer a unique opportunity to study genotype-phenotype correlation. Here, we present a three-generation family starting from a pair of monozygotic twins discordant for metachondromatosis due to postzygotic p.(Gln175His) variant in the PTPN11 gene. Both phenotypically discordant monozygotic twins harbor p.(Gln175His), however significant differences in mosaic ratio is observed not only between twins, but also within different tissue types within one individual. Phenotypic manifestation of p.(Gln175His) in examined family clearly depends on allele variant fraction (VAF). Individuals harboring constitutional mutation (VAF 50%) present typical metachondromatosis. Milder phenotype is observed in twin harboring high-level mosaicism in the tissue of ectodermal origin (VAF 45%), but not in a blood (VAF 5%). Finally, her twin sister harboring low-level mosaicism in blood (VAF 2%) and nonblood (VAF 12%) tissues is phenotypically normal. Our results provide insights into biological role of mosaicism in disease and further support the usefulness of nonblood tissues as an optimal source of DNA for the identification of postzygotic mutations in phenotypically discordant monozygotic twins.
由于其在人类疾病中的作用，合子后突变引起的遗传镶嵌现象引起了极大的关注。由单个受精卵发育而来的同卵双胞胎被认为在遗传上是相同的，任何差异很可能是由合子后事件引起的。因此，表型不一致的同卵双胞胎为研究基因型-表型相关性提供了独特的机会。在这里，我们介绍了一个三代家族，其起源于一对同卵双胞胎，由于 PTPN11 基因中的 p.(Gln175His) 变异导致后生骨软骨瘤病表型不一致。表型不一致的同卵双胞胎均携带 p.(Gln175His)，然而，不仅在双胞胎之间，而且在一个个体的不同组织类型之间，都观察到镶嵌率的显著差异。在检查的家族中，p.(Gln175His) 的表型表现显然取决于等位基因变异分数 (VAF)。携带构性突变 (VAF 50%) 的个体表现出典型的后生骨软骨瘤病。在组织中携带高水平镶嵌性的双胞胎中观察到较轻的表型 (VAF 45%)，但在血液中则没有 (VAF 5%)。最后，她的双胞胎姐姐在血液 (VAF 2%) 和非血液 (VAF 12%) 组织中携带低水平镶嵌性，表型正常。我们的结果深入了解了镶嵌现象在疾病中的生物学作用，并进一步支持非血液组织作为鉴定表型不一致的同卵双胞胎中合子后突变的最佳 DNA 来源的有用性。
