Complex rearranged small supernumerary marker chromosomes (sSMC), three new cases; evidence for an underestimated entity?

Abstract

Background: Small supernumerary marker chromosomes (sSMC) are present ~2.6 x 106 human worldwide. sSMC are a heterogeneous group of derivative chromosomes concerning their clinical consequences as well as their chromosomal origin and shape. Besides the sSMC present in Emanuel syndrome, i.e. der(22)t(11;22)(q23;q11), only few so-called complex sSMC are reported.

Results: Here we report three new cases of unique complex sSMC. One was a de novo case with a dic(13 or 21;22) and two were maternally derived: a der(18)t(8;18) and a der(13 or 21)t(13 or 21;18). Thus, in summary, now 22 cases of unique complex sSMC are available in the literature. However, this special kind of sSMC might be under-diagnosed among sSMC-carriers.

Conclusion: More comprehensive characterization of sSMC and approaches like reverse fluorescence in situ hybridization (FISH) or array based comparative genomic hybridization (array-CGH) might identify them to be more frequent than only ~0.9% among all sSMC.

Figure 1

Cytogenetic and molecular cytogenetic results of case A (= case 13 in Tab.1). The marker is highlighted by a blue arrowhead in a, d, e and f. a) GTG-banding revealed a karyotype 47,XY,+mar in all studied cells. b) Chromosome flow sorting and reverse FISH revealed that the sSMC [= der(18)] consists of chromosome 18p and 8pter material. c) The result of reverse FISH was confirmed by a subtelomeric probe for 8pter (green) and the centromeric probe D18Z1 (= cep 18 – red). d) A subtelomeric probe for 18pter (green) together with D18Z1 (cep 18 – red) indicated that the entire short arm of chromosome 18 was present on the marker chromosome. e) Application of probe D18Z1 with the centromere-near probes for 18p11.21 and 18q11.2 with the showed that obviously no 18q-material was present on the sSMC. f) Multicolor banding (MCB) confirmed that the whole short arm was present three times in this case. There was no hint on additional material of other chromosomal material on the sSMC by this approach.

Figure 2

a) Molecular cytogenetics revealed in case B (= case 16 in Tab. 1) that the sSMC was derived from chromosome 13 or 21, as the centromeric probe (D13/21Z1 – green) and a probe specific for all acrocentric p-arms (midi54 – blue) were present on the marker. However, no centromere-near material, neither from chromosome 13 nor 21 was detectable on the marker (pink and red probes). b) Three-color-FISH using partial chromosome painting (pcp) probe for the short (green) and the long arm of chromosome 18 (blue) together with a probe for the centromere-near region of 18p11.2 (red) revealed that the whole short arm was present on the sSMC.

Figure 3

a) On the sSMC of case C (= case 10 in Tab.1– marked by blue arrowhead throughout whole figure) a signal for D13/21Z1 (cep 13/21-green) and two signals for a probe specific for all acrocentric p-arms (midi54 – blue) was obtained. b) Combining the centromeric probe D14/22Z1 (cep 14/22 – green) with midi54 (blue) and a centromere-near probe in 22q11.21 a tetrasomy of this region was detected. c) The size of the duplication was determined by application of two further probes located in 22q11.21 and 22q11.22.

Figure 4

Involvement of the 24 different human chromosomes into the formation of unique complex sSMC.

Figure 5

Origin of unique complex sSMC: de novo, maternal or due to a parental translocation (parental t).

Figure 6

Clinical outcome of 19 of the 22 cases with a unique complex sSMC.