Germ line mosaicism

Abstract

Mosaicism in germ cells has been recognized, over the past few years, as an important and relatively frequent mechanism at the origin of genetic disorders. There are two possibilities for the existence of such a mosaicism: one is that the mutation occurs in a germ cell that continues to divide. The other possibility is that the mutation occurs very early in a somatic cell before the separation to germinal cells and is therefore present both in somatic and germinal cells. Depending on various factors, such as the gene involved and/or the degree of mosaicism, the carrier of a somatic and germline mosaicism may be asymptomatic or may present with various symptoms of the disease. There are still relatively few reports in the literature in which the origin of germ-line mosaicism has been analyzed; nevertheless, they allow for a better insight into the mechanisms involved. In some diseases, such as osteogenesis imperfecta, new mutations are often present as asymptomatic somatic and germline mosaicism in one of the parents of the propositus. In other disorders, such as neurofibromatosis, somatic mosaicism is very rare in the parents of the propositus, perhaps since such mosaicism causes clinical symptoms. These differences are particularly important for genetic counseling in order to evaluate the risk for another affected child after the birth of the propositus.

Germline and gonosomal mosaicism in the ATR-X syndrome

“…Zlotogora, in a review of the literature, 9 distinguished two groups of diseases: group 1 in which somatic and germline mosaicism in one of the unaffected parents is relatively frequent, and group 2 in which mosaisicm is almost never found. ATR-X joins the group of conditions, eg fascioscapulohumeral dystrophy, haemophilia, Christmas disease, osteogenesis imperfecta and Duchenne muscular dystrophy, where post-zygotic mutation is relatively 'common' 9 and germline mosaicism is an important consideration in the counselling of parents of sporadic cases when the mutation is not detected in the mother.…”

Penetrance and expressivity in the molecular age

“…The absence of symptoms in the parents is due to the presence of a mutation in the germ cells with or without a mosaicism in the somatic cells. 2 …”

Recurrence of Mowat–Wilson syndrome in siblings with the same proven mutation

“…Germ-line mosaicism is a well-described phenomenon and has been reported in many autosomal dominant conditions due to intragenic mutations, including osteogenesis imperfecta, tuberous sclerosis, and achondroplasia [Zlotogora, 1998;Rose , 1999]. While theoretical methods to estimate the risk of recurrence due germ-line mosaicism have been outlined [van der Meulen et al, 1995], empiric recurrence risks where parents are clinically unaffected vary significantly in different disorders, from <1% in achondroplasia to 6% in osteogenesis imperfecta [Zlotogora, 1998;Mettler and Fraser, 2000].…”

“…While theoretical methods to estimate the risk of recurrence due germ-line mosaicism have been outlined [van der Meulen et al, 1995], empiric recurrence risks where parents are clinically unaffected vary significantly in different disorders, from <1% in achondroplasia to 6% in osteogenesis imperfecta [Zlotogora, 1998;Mettler and Fraser, 2000]. Little is known about the mechanisms underlying germinal þ/À somatic mosaicism in new dominant disorders, but molecular analyses in several conditions have shown that somatic mosaicism in an apparently unaffected parent is not uncommon where more than one child is affected [Zlotogora, 1998]. This is the first time presumed germ-line mosaicism has been described in MWS, with over 50 mutation positive cases reported in the literature so far, but stresses the importance of including this possibility when counseling parents of a single affected child.…”