Chapter 3.4 Mosaicism with a normal cell line and an unbalanced autosomal reciprocal translocation; three new cases and review of the literature

Mosaicism involving a normal cell line and an unbalanced autosomal translocation are rare. In this study we present three new cases detected by Single Nucleotide Polymorphism (SNP) array analysis in our routine diagnostic setting. These cases were further characterized using Fluorescence in situ Hybridisation (FISH) analysis and conventional karyotyping. The first case is a mentally retarded male who carries an unbalanced translocation in 87% of his cells. Remarkably, the phenotypically normal mother carries the balanced form of the translocation in all her cells. The second case is a phenotypically normal female who has an unbalanced translocation in 52% of her cells. She passed the unbalanced translocation to her daughter who has mild mental retardation and serious behavior disturbance. The third case is a female referred for Rubinstein-Taybi syndrome who carries a complex unbalanced translocation in 60% of her cells. Her mother showed a normal karyotype. The mechanisms that might be responsible for these mosaic karyotypes are discussed. Furthermore, we demonstrate that high-resolution whole-genome array is a powerful tool to reveal cryptic unbalanced translocations and mosaicisms, including the more rare cases. Introduction Mosaicism is the presence of genetically different cell lines in one individual derived from a single zygote. Mosaicism can be caused by several mechanisms, including chromosomal abnormalities and DNA mutations (reviewed by Youssoufian and Pyeritz, 2002). Whether a mosaicism is disease-causing depends upon the abnormality, on which tissue is abnormal and on how much of a tissue is affected. If only a fraction of the soma is abnormal (somatic mosaicism), the phenotype is likely to be normal and will probably never be recognized (Gardner et al., 1994). If it involves a substantial part of the soma, it can cause dysmorphisms and malformation, and if the brain is included, mental retardation (MR). Abnormality involving only a part of the gonad (gonadal mosaicism) is not associated with an abnormal phenotype of the carrier and will usually only be recognized after two siblings are born with the same ‘de novo’ abnormality (Youssoufian and Pyeritz, 2002). Chimerism is the presence of genetically different cell lines in one individual derived from two or more different zygotes. If both cell lines contain the same sex chromosomes, conventional karyotyping is generally not able to distinguish between mosaicism and chimerism. Support for the mechanism causing two or more different cell lines as a result of chimerism can be obtained by comparison of DNA microsatellite markers (Cotter and Hirschhorn, 1998). Somatic mosaicism with an abnormal cell line can be missed by conventional karyotyping if masked by a high percentage of normal cells or even dismissed as a culture artefact (Ballif et al., 2006). Additionally, healthy individuals with a mosaicism will in most cases not be investigated. The prevalence of mosaicisms is therefore difficult to establish. Lebbar et al. (2008) reviewed the literature for mosaicism with a normal cell line and a balanced rearrangement and reported 35 cases. Most of these carriers have a normal phenotype and were referred due to recurrent miscarriages, infertility or the birth of an abnormal child. Furthermore, they described the first two cases of mosaicism for a normal cell line and a complex chromosome rearrangement (CCR) in patients ascertained through infertility. Zaslav and colleagues (1999) reported