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オープンアクセス

概要

The Importance of Germline Mosaicism in the Occurrence of De novo Mutational Events and its Necessary Diagnosis

Celine Chalas, Catherine Patrat

For long, germline mosaicism has been considered a very rare event whereas it was in fact underestimated because of its lack of diagnosis. Thanks to the development of NGS (next generation sequencing) applied to intergeneration studies; its occurrence is now better diagnosed. Genomic variations characteristic of this phenomenon can be either Single Nucleotide Polymorphism (SNP) or Copy Number Variations (CNV). De novo mutations resulting in germline mosaicism can appear either pre or postzygotically. If the mutation occurs postzygotically, the mutation may exist in the germ cells but also in the soma. In that case, the mosaic carrier is healthy because of the low level of expression of the mutation. However, the mutation will be transmitted to all cells of the offspring that will express the disease. On the contrary, if the mutational event occurs prezygotically in the germ cells than there is no expression in the soma. The risk of transmission to the offspring will rely on the percentage of germ cells carrying the deletion. In particular, in the paternal germline, it has been shown that this risk increases with paternal age and is referred as paternal age effect. Indeed, the Spermatogonial Stem Cell (SSC) pool is maintained through a high rate of cell divisions throughout a men’s lifespan, with hence a higher risk of errors from mitosis as the individual ages. In some cases, the acquired mutation gives a growth advantage to SSCs, leading to the clonal expansion of mutated cells in the testis and thereby increasing the number of spermatozoa carrying the pathogenic mutations. In that case, the best diagnosis would be to perform sperm analysis to ascertain the diagnosis and to evaluate the accurate risks of transmission. Therefore, there is a necessary need to develop routine diagnosis on sperm to search for germline mosaicism.