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Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification

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Abstract

Small supernumerary marker chromosomes (SMCs) are present in about 0.05% of the human population. In approximately 30% of SMC carriers (excluding the ~60% SMC derived from one of the acrocentric chromosomes), an abnormal phenotype is observed. The clinical outcome of an SMC is difficult to predict as they can have different phenotypic consequences because of (1) differences in euchromatic DNA-content, (2) different degrees of mosaicism, and/or (3) uniparental disomy (UPD) of the chromosomes homologous to the SMC. Here, we present 35 SMCs, which are derived from all human chromosomes, apart from chromosome 6, as demonstrated by the appropriate molecular cytogenetic approaches, such as centromere-specific multicolor fluoresence in situ hybridization (cenM-FISH), multicolor banding (MCB), and subcentromere-specific multicolor FISH (subcenM-FISH). In nine cases without an aberrant phenotype, neither partial proximal trisomies nor UPD could be detected. Abnormal clinical findings, such as psychomotoric retardation and/or craniofacial dysmorphisms, were associated with seven of the cases in which subcentromeric single-copy probes were proven to be present in three copies. Conversely, in eight cases with a normal phenotype, proximal euchromatic material was detected as partial trisomy. UPD was studied in 12 cases and subsequently detected in two of the cases with SMC (partial UPD 4p and maternal UPD 22 in a der(22)-syndrome patient), indicating that SMC carriers have an enhanced risk for UPD. At present, small proximal trisomies of 1p, 1q, 2p, 6p, 6q, 7q, 9p, and 12q seem to lead to clinical manifestations, whereas partial proximal trisomies of 2q, 3p, 3q, 5q, 7p, 8p, 17p, and 18p may not be associated with significant clinical symptoms. With respect to clinical outcome, a classification of SMCs is proposed that considers molecular genetic and molecular cytogenetic characteristics as demonstrated by presently available methods.

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Fig. 3. Fig. 4a, b. Fig. 5.

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Acknowledgements

This work was supported by the Robert-Pfleger-Stiftung (Bamberg, Germany), Herbert Quandt Stiftung der VARTA, and the EU (ICA2-CT-2000-10012). We thank Dr. Lisa Shaffer (Spokane, USA), Dr. Jasen Anderson (Brisbane, Australia), and Dr. Joris Vermeesch (Leuven, Belgium) for helpful discussions. The continuous support of the Carl Zeiss (Jena, Germany) is gratefully acknowledged.

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Authors and Affiliations

  1. Institut für Humangenetik und Anthropologie, Kollegiengasse 10, 07743, Jena, Germany

    Heike Starke, Angela Nietzel, Anja Weise, Anita Heller, Kristin Mrasek, Alma Kuechler, Isolde Schreyer, Uwe Claussen, Ferdinand von Eggeling & Thomas Liehr

  2. Praxis für Medizinische Genetik, Frankfurter Allee 111, 10247, Berlin, Germany

    Britta Belitz

  3. Praxis für Medizinische Genetik, Marienstrasse 27, 03046, Cottbus, Germany

    Christine Kelbova

  4. Institut für Humangenetik, Leipziger Strasse 44, 39120, Magdeburg, Germany

    Marianne Volleth

  5. Institut für Humangenetik, Hufelandstrasse 55, 45122, Essen, Germany

    Beate Albrecht

  6. Zentralklinikum Suhl, gGmbH, A.-Schweitzer-Strasse 2, 98527, Suhl, Germany

    Beate Mitulla

  7. Institut für Humangenetik, Zentrum für Hygiene und Humangenetik, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany

    Ralf Trappe & Iris Bartels

  8. Olgahospital, Institut für Klinische Genetik, Bismarkstrasse 3, 70176, Stuttgart, Germany

    Sabine Adolph

  9. Institut für Humangenetik und Anthropologie, Wilhelmstrasse 27, 72074, Tübingen, Germany

    Andreas Dufke & Sylke Singer

  10. Partnerschaft für Medizinische Genetik, Kurfürstendamm 199, 10719, Berlin, Germany

    Markus Stumm & Rolf-Dieter Wegner

  11. Klinik für Kinder- und Jugendmedizin, Kochstrasse 2, 07743, Jena, Germany

    Jörg Seidel

  12. Praxis für Humangenetik, Podbielskistrasse122, 30177, Hannover, Germany

    Angela Schmidt

  13. Klinik für Strahlentherapie, Bachstrasse 18, 07743, Jena, Germany

    Alma Kuechler

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  1. Heike Starke
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  2. Angela Nietzel
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Correspondence to Thomas Liehr.

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Electronic database information: accession numbers and URLs for the data in this article are as follows:

ENSEMBL-database, http://www.ensembl.org/

National Center for Biotechnology Information (NCBI), http://www.ncbi.nlm.nih.gov/

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OMIM (Online Mendelian Inheritance in Man) Database, http://www.ncbi.nlm.nih.gov/omim

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Starke, H., Nietzel, A., Weise, A. et al. Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification. Hum Genet 114, 51–67 (2003). https://doi.org/10.1007/s00439-003-1016-3

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