Mechanisms of Origin and Clinical Effects of Multiple Small Supernumerary Marker Chromosomes, Each Derived from a Different Chromosome

Abstract

Small supernumerary marker chromosomes (sSMCs) are centric chromosome fragments additionally present in an otherwise normal human chromosome set that cannot be characterized by classical cytogenetic techniques alone. The majority of sSMCs are not yet related to a defined clinical phenotype. We compiled from the literature all 78 cases with multiple sSMCs per cell in which the chromosomal origin of the sSMCs has been identified. The number of sSMCs varies from 2 to 7; 64% have 2 sSMCs, 14% have 3 sSMCs, and the frequency decreases to 3% each for cases with 6 or 7 sSMCs. We propose that the majority of cases originate from premature separation of sister chromatids during maternal meiosis I or II, leading to multiple trisomies in the zygote. Because ~80% of single sSMCs and ~64% of sSMCs in cases with multiple sSMCs have at least one break in the centromere, we further propose that aberrant kinetochore-spindle attachment during maternal meiosis leads to breaks within or close to the centromeres of the additional chromosomes. The resulting sSMCs are mitotically stable if they contain a sufficient amount of alpha satellite repeats for proper centromere function and if the double strand breaks are repaired either by ring chromosome formation or by telomere capture or synthesis. This model is supported by observations on fertilized oocytes, polar bodies and blastomeres, which show that 2 to 7 additional chromosomes of different origin can occur in human zygotes. In addition, observations on double trisomies in cases of spontaneous abortion show that these are almost invariably of maternal origin and involve two segregation errors either during meiosis I or II, or two consecutive errors, one during meiosis I and the other during meiosis II. This model explains why all chromosomes can contribute to one of the multiple sSMCs, why each case has a unique combination of sSMCs with respect to the chromosomes of origin, why there is a maximum number of up to 6-7 sSMCs per cell, why the number of cases is inversely proportional to the number of sSMCs per cell and why all cases in which this was studied occurred de novo. We further propose that cases with a paternal origin are much rarer and result from meiotic errors that lead to sperm cells with multiple additional chromosomes. Recent studies of the parental origin of de novo multiple sSMCs in 5 patients show a maternal origin in 4 cases, involving either multiple meiosis I or II segregation errors, and a paternal origin in one case. Multiple sSMCs can lead to highly variable and complex clinical phenotypes if they contain dosage-sensitive genes. Phenotypes are further complicated by the somatic mosaicism of the sSMCs due to mitotic loss, as seen in 92% of cases. In 12.5% of postnatal and 38% of prenatal cases there are no or only very mild clinical abnormalities. Therefore, during clinical management of the pregnancy, the gene content and degree of mosaicism must be carefully evaluated for each of the multiple sSMCs.