A new small supernumerary marker chromosome, generating mosaic pure trisomy 16q11.1–q12.1 in a healthy man
© Rodríguez et al; licensee BioMed Central Ltd. 2008
Received: 26 October 2007
Accepted: 02 April 2008
Published: 02 April 2008
Here we report on a healthy and fertile 30 years old man, who was carrier of a small supernumerary marker chromosome (sSMC). The application of molecular techniques such as fluorescence in situ hybridisation (FISH), microdissection and reverse painting, helped to characterize the sSMC which resulted to be derived from chromosome 16. In fact, the presence of euchromatin material from the long arm (16q) in the sSMC was demonstrated, and the karyotype can be written as mos 47, XY,+min(16)(:p11.1->q12.1:)/46, XY .
Small supernumerary marker chromosomes (sSMC) have been recently defined by Liehr et al.  as "structurally abnormal chromosomes that cannot be identified or characterized unambiguously by conventional banding cytogenetics alone, and generally are equal in size or smaller than a chromosome 20 of the same metaphase spread". These sSMC have been described from all human chromosomes although most of them are derivatives of acrocentric chromosomes [1, 2], and approximately 30% of them were parentally inherited [3, 4].
The individuals carrying a sSMC, have a wide range of clinical variability, which may be related with the different sizes of the sSMC, the presence and/or absence of euchromatic material, the degree of mosaicism and/or uniparental disomy (UPD) . Indeed, 70% of non-acrocentric sSMC do not have phenotypic repercussion, while the remaining 30% have different clinical manifestations . Therefore, it is very important to characterize the content and the structure of the sSMC, in order to establish an adequate genotype-phenotype correlation.
The chromosome 16 long arm (16q) is characterized by the presence of a block of heterochromatin located between its centromere and the euchromatin region. Trisomy of the heterochromatin block is not related with any clinical manifestations, in fact there are five reported cases with sSMC (16), whose content is limited to the centromeric D16Z and heterochromatin regions without clinical manifestations. Among these five cases, the first one, had an abnormal phenotype attributed to an obstetric trauma . The second case ended in a termination of pregnancy (TOP) with no clinical information . And finally, the other three cases were ascertained in the amniotic fluid of three pregnant woman being normal the prenatal outcome and/or baby follow-up [11–13].
Trisomy of the next euchromatic region of the long arm of chromosome 16 (involving the q12 band) has been reported in seven case reports and seven members of two families [14–20] and after a recent review of the clinical data from all those patients, Barber et al.  concluded that "duplications of proximal 16q do not have characteristic facies but frequently have short stature, developmental delay, speech delay, learning difficulties and behavioural problems which range from mild to severe". A few genes has been located at 16q12-13 band, such as the Hereditary cylindromatosis gene (CYLD1), which has been defined as a tumor suppressor gene , the beta subunit gene of the Phosphorylase kinase (PHKB) which is an enzyme that activates glycogen phosphorylases in muscle, liver, and other tissues  and the human smooth muscle myosin heavy chain (MHC) which corresponds to MYH11 gene, and is expressed in the human umbilical artery, bladder, esophagus and trachea .
The case we present here, has a partial trisomy of the long arm of chromosome 16, involving the heterochromatin block and the proximal euchromatin region at 16q12 band, and as far as we know is the first one reported in a phenotypically normal patient, with no developmental delay neither mental retardation. It was produced "de novo", and consequently we could not disregard that it could be due to low repetitive elements present in the pericentromeric region of chromosome 16, as recently proposed by different authors for chromosomes 2, 10 and 12 [24–26]. And it was found as a mosaicism, although other tissues were not studied, where different degrees of mosaicism may be present influencing the patient phenotype.
In conclusion, the advantage of molecular techniques have allowed to know the real euchromatic/heterochromatic content of the sSMC(16) in our patient. In fact, they helped to show that not all the euchromatic trisomies are associated with clinical repercussion, as previously reported by Barber . Nevertheless, more affected and non-affected patients are needed to be described in order to elucidate the phenotype-genotype correlations of different sSMC, that we consider is essential for a right genetic prenatal counselling.
We thank the family and their physicians for their collaboration in this study. This work was supported by a Grant (PI020028) from the Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III. Ministerio de Sanidad y Consumo. Spain.
- Liehr T, Claussen U, Starke H: Small supernumerary marker chromosomes (sSMC) in humans. Cytogenet Genome Res 2004, 107: 55–67. 10.1159/000079572View ArticlePubMedGoogle Scholar
- Liehr T, Mrasek K, Weise A, Dufke A, Rodriguez L, Martinez Guardia N, Sanchis A, Vermeesch JR, Ramel C, Polityko A, Haas OA, Anderson J, Claussen U, von Eggeling F, Starke H: Small supernumerary marker chromosomes – progress towards a genotype-phenotype correlation. Cytogenet Genome Res 2006, 112: 23–34. 10.1159/000087510View ArticlePubMedGoogle Scholar
- Dennis NR, Veltman MW, Thompson R, Craig E, Bolton PF, Thomas NS: Clinical findings in 33 subjects with large supernumerary marker(15) chromosomes and 3 subjects with triplication of 15q11-q13. Am J Med Genet A 2006, 140: 434–41.View ArticlePubMedGoogle Scholar
- Liehr T, Weise : A Frequency of small supernumerary marker chromosomes in prenatal, newborn, developmentally retarded and infertility diagnostics. Int J Mol Med 2007, 19: 719–31.PubMedGoogle Scholar
- Crolla JA, Dennis NR, Jacobs PA: A non-isotopic in situ hybridisation study of the chromosomal origin of 15 supernumerary marker chromosomes in man. Journal of Medical Genetics 1992, 29: 699–703.PubMed CentralView ArticlePubMedGoogle Scholar
- Starke H, Nietzel A, Weise A, Heller A, Mrasek K, Belitz B, Kelbova C, Volleth M, Albrecht B, Mitulla B, Trappe R, Bartels I, Adolph S, Dufke A, Singer S, Stumm M, Wegner RD, Seidel J, Schmidt A, Kuechler A, Schreyer I, Claussen U, von Eggeling F, Liehr T: Small supernumerary marker chromosomes (SMC): genotype-phenotype correlation and classification. Hum Genet 2003, 114: 51–67. 10.1007/s00439-003-1016-3View ArticlePubMedGoogle Scholar
- Starke H, Raida M, Trifonov V, Clement JH, Loncarevic IF, Heller A, Bleck C, Nietzel A, Rubtsov N, Claussen U, Liehr T: Molecular cytogenetic characterization of an acquired minute supernumerary marker chromosome as the sole abnormality in a case clinically diagnosed as atypical Philadelphia-negative chronic myelogenous leukaemia. Br J Haematol 2001, 113: 435–8. 10.1046/j.1365-2141.2001.02787.xView ArticlePubMedGoogle Scholar
- Tönnies H, Pietrzak J, Bocian E, MacDermont K, Kuechler A, Belitz B, Trautmann U, Schmidt A, Schulze B, Rodriguez L, Binkert F, Yardin C, Kosyakova N, Volleth M, Mkrtchyan H, Schreyer I, von Eggeling F, Weise A, Mrasek K, Liehr T: New immortalized cell lines of patients with small supernumerary marker chromosome: towards the establishment of a cell bank. J Histochem Cytochem 2007, 55(6):651–60. 10.1369/jhc.6A7161.2007View ArticlePubMedGoogle Scholar
- Callen DF, Ringenbergs ML, Fowler JC, Freemantle CJ, Haan E: A Small marker chromosomes in man: origin from pericentric heterochromatin of chromosomes 1, 9, and 16. J-Med-Genet 1990, 27: 155–9.PubMed CentralView ArticlePubMedGoogle Scholar
- Callen DF, Eyre HJ, Ringenbergs ML, Freemantle CJ, Woodroffe P, Haan EA: Chromosomal origin of small ring marker chromosomes in man: characterization by molecular genetics. Am J Hum Genet 1991, 48: 769–782.PubMed CentralPubMedGoogle Scholar
- Crolla JA: FISH and molecular studies of autosomal supernumerary marker chromosomes excluding those derived from chromosome 15: II. Review of the literature. Am J Med Genet 1998, 75: 367–81. 10.1002/(SICI)1096-8628(19980203)75:4<367::AID-AJMG5>3.0.CO;2-NView ArticlePubMedGoogle Scholar
- Paoloni-Giacobino A, Morris MA, Dahoun SP: Prenatal supernumerary r(16) chromosome characterized by multiprobe FISH with normal pregnancy outcome. Prenat Diagn 18(7):751–2. 10.1002/(SICI)1097-0223(199807)18:7<751::AID-PD312>3.0.CO;2-5
- Sanz R, Anabitarte MA, Querejeta ME, Lorda-Sanchez I, Ibanez MA, Rodriguez de Alba MR, Ayuso C, Ramos C: Rapid identification of a small dicentric supernumerary marker derived from chromosome 16 with a modified FISH technique on amniotic fluid. Prenat Diagn 2000, 20: 63–5. 10.1002/(SICI)1097-0223(200001)20:1<63::AID-PD741>3.0.CO;2-WView ArticlePubMedGoogle Scholar
- Hirai S, Ujüe J, Suzuki J, Ishiyama S, Tsukanishi A, Muramoto J, Kano H, Suzuki H: Duplication of the long arm of chromosome 16. Jpn J Pédiatr 1981, 34: 1963–1967.Google Scholar
- Romain DR, Frazer AG, Columbano-Green LM, Parfitt RG, Smythe RH, Chapman CJ: Direct intrachromosomal duplication of 16q and heritable fragile site fra (10) (q25) in the same patient. Am J Med Genet 1984, 19: 507–13. 10.1002/ajmg.1320190312View ArticlePubMedGoogle Scholar
- Fryns JP, Kleczkowska A, Decock P, Van den Berghe H: Direct duplication 16q11.1–16q13 is not associated with a typical dysmorphic syndrome. Ann Genet 1990, 33: 46–8.PubMedGoogle Scholar
- Mascarello JT, Hubbard V: Routine use of methods for improved G-band resolution in a population of patients with malformations and developmental delay. Am J Med Genet 1991, 38: 37–42. 10.1002/ajmg.1320380110View ArticlePubMedGoogle Scholar
- Engelen JJ, De Die-Smulders CE, Vos PT, Meers LE, Albrechts JC, Hamers AJ: Characterization of a partial trisomy 16q with FISH. Report of a patient and review of the literature. Ann Genet 1999, 42: 101–4.PubMedGoogle Scholar
- Trimborn M, Wegner RD, Tönnies H, Sarioglu N, Albig M, Neitzel H: Prenatal diagnosis and molecular cytogenetic characterisation of a small de novo interstitial duplication 16q11.2-q13. Prenat Diagn 2006, 26: 273–6. 10.1002/pd.1396View ArticlePubMedGoogle Scholar
- Barber JC, Zhang S, Friend N, Collins AL, Maloney VK, Hastings R, Farren B, Barnicoat A, Polityko AD, Rumyantseva NV, Starke H, Ye S: Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect. Cytogenet Genome Res 2006, 114: 351–8. 10.1159/000094225View ArticlePubMedGoogle Scholar
- Thomson SA, Rasmussen SA, Zhang J, Wallace MR: A new hereditary cylindromatosis family associated with CYLD1 on chromosome 16. Hum Genet 1999, 105: 171–3. 10.1007/s004390051083View ArticlePubMedGoogle Scholar
- Francke U, Darras BT, Zander NF, Kilimann MW: Assignment of human genes for phosphorylase kinase subunits alpha (PHKA) to Xq12-q13 and beta (PHKB) to 16q12-q13. Am J Hum Genet 1989, 45: 276–82.PubMed CentralPubMedGoogle Scholar
- Matsuoka R, Yoshida MC, Furutani Y, Imamura S, Kanda N, Yanagisawa , Masaki T, Takao A: Human smooth muscle myosin heavy chain gene mapped to chromosomal region 16q12. Am J Med Genet 1993, 46: 61–7. 10.1002/ajmg.1320460110View ArticlePubMedGoogle Scholar
- Jackson MS, Rocchi M, Thompson G, Hearn T, Crosier M, Guy J, Kirk D, Mulligan L, Ricco A, Piccininni S, Marzella R, Viggiano L, Archidiacono N: Sequences flanking the centromere of human chromosome 10 are a complex patchwork of arm-specific sequences, stable duplications and unstable sequences with homologies to telomeric and other centromeric locations. Hum Mol Genet 1999, 2: 205–15. 10.1093/hmg/8.2.205View ArticleGoogle Scholar
- Vermeesch JR, Duhamel H, Raeymaekers P, Van Zand K, Verhasselt P, Fryns JP, Marynen P: A physical map of the chromosome 12 centromere. Cytogenet Genome Res 2003, 103: 63–73. 10.1159/000076291View ArticlePubMedGoogle Scholar
- Mrasek K, Starke H, Liehr T: Another small supernumerary marker chromosome (sSMC) derived from chromosome 2: towards a genotype/phenotype correlation. J Histochem Cytochem 2005, 53: 367–70. 10.1369/jhc.4B6414.2005View ArticlePubMedGoogle Scholar
- Barber J: Directly transmitted unbalanced chromosome abnormalities and euchromatic variants. J Med Genet 2005, 42: 609–629. 10.1136/jmg.2004.026955PubMed CentralView ArticlePubMedGoogle Scholar
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