Published on July 30, 2020   35 min

Other Talks in the Series: Introduction to Human Genetics and Genomics

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My name is Eamonn Maher, I'm a Professor of Medical Genetics and Genomic Medicine and Honorary Consultant in Clinical Genetics in the Department of Medical Genetics at the University of Cambridge and Cambridge University Hospitals NHS Trust. I'd like to speak about Mosaicism.
An individual with a genetic alteration in some of their cells is mosaic for the relevant genetic alteration. Some mosaicism arises after fertilisation and should be distinguished from chimerism which is extremely rare, the condition in which there are two genetically distinct cell populations from two different individuals. For example, if two embryos fuse, this would result in a chimera. Mosaicism has long been recognised in specific situations. For example, as we had in the lecture on X-linked inheritance, the random X chromosome inactivation that occurs in normal females means that they can be considered mosaic as they have two cell populations that differ according to which X chromosome is silenced. As we'll see later, this can be of medical significance if one X chromosome carries a pathogenic variant in an X-linked dominant disease gene. When cytogeneticists undertake routine analysis for chromosomal abnormalities, they will look at multiple cells. Mosaicism for chromosomal disorders such as Turner syndrome, also known as 45,X, has long been recognised. Indeed, if chromosomal mosaicism is suspected then the cytogeneticists will greatly increase the number of cells analysed so that lower levels of mosaicism might be detected. Mosaicism for single gene disorders also occurs, but until relatively recently has been under diagnosed. However, with the advent of next-generation sequencing techniques or other specialist techniques that have been developed to detect low levels of mosaicism for single gene mutations, the frequency of recognised cases of mosaicism in many disorders has increased, because these new techniques are more sensitive than the conventional Sanger sequencing, which had previously been used for routine diagnosis for most monogenic disorders. As we will see, the clinical consequences of mosaicism are very variable. But in general, an individual who is mosaic for a disorder will have a milder phenotype than an individual who carries the genetic alteration in all of their cells. However, there are some mosaic disorders that cause a severe clinical phenotype. In these cases, non-mosaic individuals are not seen, and presumably the non-mosaic cases are not viable.