Small supernumerary marker chromosomes: a legacy of trisomy rescue?

We studied by a whole cytogenomics approach 12 de novo, non-recurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis. In 11 cases maternal age was increased. Trios genotyping, WGS, and CGH+SNP array, demonstrated that (i) four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event; (ii) in four cases maternal hetero/isodisomy was detected with a sharp paternal origin of the sSMC in two cases, whereas in a fifth case two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In five other cases the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. In one case, the sSMC was of paternal origin while the homologs were biparental. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic non-disjunction followed by post-zygotic anaphase lagging of the supernumerary chromosome and its subsequent insertion within a micronucleus, whose segregation to one of the two daughter cells accounts for the mosaic condition. The sequential micronuclear shattering, re-embedding of the fragmented chromosomal material into the main nucleus where repair occurs, and loss of some fragments, explains both the disordered assembly of most sSMCs and the occurrence of maternal UPD. This mechanism identifies a link between numerical and structural chromosomal anomalies and underlines that genetic counselling in prenatally detected sSMCs will be problematic.