LETTER TO JMG Supernumerary marker chromosomes (SMC) and uniparental disomy (UPD): coincidence or consequence?

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. Mechanisms of formation are trisomy rescue, monosomy rescue, post-fertilisation errors, and gamete complementation. Problems associated with UPD include trisomy mosaicism, genomic imprinting, homozygosity of autosomal recessive mutations, or even a combination of these. Supernumerary marker chromosomes (SMCs) are predominant in only a proportion of cells leading to a specific kind of trisomy mosaicism. The presence of a cell line with two normal chromosomes and a second hyperploid cell line promoted speculation that people with a SMC might have an increased risk for UPD of the structurally normal homologues from which the SMC was derived. In the present article, published reports of UPD associated with a SMC as well as fundamental aspects of chromosome segregation and UPD are reviewed. Additionally, two questions will be discussed. Is the association of UPD with a SMC only coincidence or the consequence of an active mechanism? Which mechanisms are most likely for the formation of a SMC? METHODS AND RESULTS An extensive search in the Medline database showed only 19 cases of a SMC associated with UPD. Maternal UPD was found in 15 cases and paternal UPD in four cases (table 1). One case each was found for chromosomes 1, 6, 7, 9, 10, 12, 20, and 22, and 11 cases for chromosome 15, eight of them with Prader-Willi syndrome and three of them with Angelman syndrome, were found. 12–19 FISH investigations of one of the maternal UPD(15) cases indicated X chromosomal origin of the SMC. In another case, maternal UPD(22) was segmental and associated with a de novo 11;22 translocation. Analysis of the molecular results showed only two isodisomic cases in 10/15 of the maternal UPD group and also only one heterodisomic case in 3/4 of the paternal UPD group. No molecular results delineating heterodisomy versus isodisomy were reported in the remaining cases. A survey on systematic searches for UPD associated with a SMC other than inv dup(15) in postnatally ascertained cases showed only retrospective and therefore biased studies with two out of 49 cases testing positively, 7 20–23 one case with paternal UPD(6), and one case with maternal UPD(9) (table 2). In eight postnatal searches for UPD(15) in a total of 122 cases with an additional inv dup(15) and various phenotypes, 24–30 only two positive cases were found (table 3). 26 In one prenatal study, only two cases with UPD(15) out of 26 cases with an additional inv dup(15) were found (table 3). Prenatal incidence of SMC is approximately 1:2500 and approximately 30-50% originate from chromosome 15. 32 The incidence of specific markers other than inv dup(15) is not known. Most studies were performed before FISH with centromeric probes was established, and therefore the number of SMCs of unknown chromosomal origin is extremely high.