Meiotic errors followed by two parallel postzygotic trisomy rescue events are a frequent cause of constitutional segmental mosaicism

For decades, knowledge about copy number variation (CNV) in the human genome was limited to microscopically visible changes. Advances in technology have led to the discovery of submicroscopic CNVs, ranging from kilobases to megabases in size and covering up to 13% of the human genome [1,2]. These CNVs can cause recurrent genomic disorders and sporadic disease, or they can represent benign changes found in the healthy population [3,4]. Recent studies have revealed that CNVs are not only polymorphic between unrelated individuals, but also form a frequent source of somatic variation [5,6].Chromosomal mosaicism is defined as the coexistence of two or more chromosomally different cell lines in an organism which developed from a single zygote. The majority of those mosaicisms are aneuploidies. Several studies investigating in vitro fertilized embryos at the preimplantation stage demonstrated a very high number of chromosomal mosaicisms in early human embryos [7-9]. While many of these embryos will not reach the stage of implantation, some do continue to develop leading to fetal mosaicisms, confined placental mosaicism or mosaic infants. Postnatally, mosaicism is detected in 0.4-1% of patients referred for genetic diagnostic screening [10-12]. A recent study revealed that mosaic aberrations are present in about 0.8% of phenotypically normal adults [13]. In addition, mosaicism appears to be variable amongst different tissues: chromosomal aneuploidies were detected in approximately 10% of normal human brain cells [14].Segmental aneuploidies make up a significant part of mosaic chromosome anomalies. Analysis of several large series of prenatal samples by karyotyping has shown that, of the 0.25-2% mosaic cases that are detected, up to a third comprise segmental imbalances [15,16]. In postnatal clinical diagnosis of patients with developmental anomalies this increases to about half of the mosaic cases [10,17]. The majority of mosaic segmental imbalances are marker chromosomes [