The Down Syndrome critical region

  • B. L. Shapiro
Conference paper


Since the early 1970’s numerous attempts have been made to learn whether specific segments of chromosome 21, when triplicated, are responsible for the clinical condition Down syndrome (DS). Studies were reported in which positive or negative clinical diagnoses of DS were made in the presence of partial trisomy of one or another segment of the chromosome. The distal half of the long arm of 21 (21q22) possesses most of the gene transcribing sites of the chromosome. It was this region that was thought to contain loci essential to production of the clinical syndrome. Subsequent studies identified subregions of this band as “minimal” or “critical” sites necessary and sufficient to produce the clinical condition. A major problem with these assignments was that different investigators defined different critical/minimal regions. In 1994 evidence was presented in which regions of most of the long arm of chromosome 21 were said to contribute to the DS phenotype. Soon after, a report described a child with DS and partial tetrasomy of the short arm and proximal long arm of 21, segments clearly distinct from the previously identified critical areas. Thus the clinical diagnosis of DS can be made in the presence of partial aneuploidy of nearly all segments of chromosome 21. It must be concluded that no evidence exists that individual loci on 21 are singularly responsible for specific phenotypic abnormalities in DS. Without exception, each of the clinical findings associated with DS is a multifactorial trait. The analysis of each trait in DS should thus be similar to analyses of the same traits in the general population with a focus on the way aneuploidy affects expression of multifactorial characteristics.


Congenital Heart Disease Down Syndrome Partial Trisomy Syndrome Phenotype Distal 21q22 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Aula PJ, Leisti J, von Kuskull H (1973) Partial trisomy 21. Clin Genet 4: 241–251PubMedCrossRefGoogle Scholar
  2. Baeteman MA, Baret A, Courtiere A, Rebuffel P, Mattei JF (1983) Immunoreactive Cu-SOD and Mn-SOD in lymphocytes sub-populations from normal and trisomy 21 subjects according to age. Life Sci 32: 895–902PubMedCrossRefGoogle Scholar
  3. Baltimore Conference (1975) Third International Workshop on Human Gene Mapping, vol XII. Birth defects: original article series. The National Foundation, New York, 1976Google Scholar
  4. Cantu JM, Hernandez A, Plasencia L, Vaca G, Moller M, Rivera H (1980) Partial trisomy and monosomy 21 in an infant with an unusual de novo 21/21 translocation. Ann Genet 23: 183–186PubMedGoogle Scholar
  5. Cervenka J, Gorlin RJ, Djavadi GR (1977) Down syndrome due to partial trisomy 21q. Clin Genet 11: 119–121PubMedCrossRefGoogle Scholar
  6. Cox DR, Shimizu N (1991) HGM 11: Report of the committee on the genetic constitution of chromosome 21. Cytogenet Cell Genet 58: 800–826CrossRefGoogle Scholar
  7. Craig JM, Bickmore WA (1993) Chromosome bands — flavours to savour. Bioessays 15: 349–354PubMedCrossRefGoogle Scholar
  8. Crosti N, Serra A, Rigo A, Viglino P (1976) Dosage effect of SOD-A gene in 21-trisomic cells. Hum Genet 31: 197–202PubMedCrossRefGoogle Scholar
  9. Daniel A (1979) Normal phenotype and partial trisomy for the G positive region of chromosome 21. J Med Genet 16: 227–229PubMedCrossRefGoogle Scholar
  10. Daumer-Haas C, Schuffenhauer S, Walther JU, Schipper RD, Porstmann T, Korenberg JR (1994) Tetrasomy 21 pter-q22.1 and Down syndrome. Am J Med Genet 53: 359–365PubMedCrossRefGoogle Scholar
  11. Dekaban AS, Zelson J (1968) Retardation in a child with an extra submetacentric chromosome fragment and partial mongolism. J Ment Defic Res 12: 21–225Google Scholar
  12. Delabar JM, Sinet PM, Chadefaux B, Nicole A, Gegonne A, Stehelin D, Fridlansky F, Creau-Goldberg N, Turleau C, de Grouchy J (1987) Submicroscopic duplication of chromosome 21 and trisomy 21 phenotype (Down syndrome). Hum Genet 76: 225–229PubMedCrossRefGoogle Scholar
  13. Delabar JM, Theophile D, Rahmani Z, Chettouh JL, Blouin M, Preur B, Noel B, Sinet P-M (1993) Molecular mapping of twent-four features of Down syndrome on chromosome 21. Eur J Hum Genet 1: 114–124PubMedGoogle Scholar
  14. de la Chapelle A, Kovisto M, Schroder J (1973) Segregating reciprocal (4;21)(q21;q21) translocation with proposita trisomic for parts of 4q and 21. J Med Genet 10: 384–389PubMedCrossRefGoogle Scholar
  15. de la Torres JA, Sumner T, Gosalvez J, Stuppia L (1992) The distribution of genes on human chromosomes as studied by in situ nick translation. Genome 35: 890–894CrossRefGoogle Scholar
  16. Dent T, Edwards JH, Delhanty JDA (1963) A partial mongol. Lancet ii: 484–487CrossRefGoogle Scholar
  17. Emberger JM, Lloret R, Rossi D (1980) Partial trisomy with 45 chromosomes due to translocation of two chromosomes 21 onto a chromosome 14: 45,XX-14,-21,+t(14q21q21q). Ann Genet 23: 179–180PubMedGoogle Scholar
  18. Epstein CJ (1988) Specificity versus nonspecificity in the pathogenesis of aneuploid phenotypes. Am J Med Genet 29: 161–165PubMedCrossRefGoogle Scholar
  19. Feaster WW, Kwok LW, Epstein CJ (1977) Dosage effects for superoxide dismutase-1 in nucleated cells aneuploid for chromosome 21. Am J Hum Genet 29: 563–570PubMedGoogle Scholar
  20. Frants RR, Eriksson AW, Jongbloet PH, Hamers AJ (1975) Superoxide dismutase in Down syndrome. Lancet ii: 42–43CrossRefGoogle Scholar
  21. Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivili X (1995) A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet 4: 1935–1944PubMedCrossRefGoogle Scholar
  22. Ganner E, Evans HJ (1971) The relationship between patterns of DNA replication and of quinacrine fluorescence in the human chromosome complement. Chromosoma 35: 326–341PubMedCrossRefGoogle Scholar
  23. Gilles L, Ferradini C, Foos J, Pucheault J, Allard D, Sinet PM, Jerome H (1976) The estimation of red cell superoxide dismutase activity by pulse radiolysis in normal and trisomic 21 subjects. FEBS Lett 69: 55–58PubMedCrossRefGoogle Scholar
  24. Greber-Platzer S, Schatzmann-Turhani D, Wollenek G, Lubec G (1999) Evidence against the current hypothesis of “gene dosage effects” of trisomy 21: ets-2, encoded on chromosome 21” is not overexpressed in hearts of patients with Down syndrome. Biochem Biophys Res Comm 254: 395–399PubMedCrossRefGoogle Scholar
  25. Groner Y, Elroy-Stein O, Avraham KB, Schickler M, Knobler H, Minc-Golomb D, Bar-Peled O, R Yaron, Rotshenker S (1994) Cell damage by excess CuZnSOD and Down’s syndrome. Biomed Pharmacother 48: 231–240PubMedCrossRefGoogle Scholar
  26. Habedank M, Rodewald A (1982) Moderate Down’s syndrome in three siblings having partial trisomy 21q22.2 → qter and therefore no SOD-1 excess. Hum Genet 60: 74–77PubMedCrossRefGoogle Scholar
  27. Hagemeijer A, Smit EME (1977) Partial trisomy 21. Further evidence that trisomy of band 21q22 is essential for Down’s phenotype. Hum Genet 38: 15–23PubMedCrossRefGoogle Scholar
  28. Hernandez D, Pannett AA, Tybulewicz V, Fisher EM (1995) Highly polymorphic sequence at D21S1448 mapping close to D21S55, within the Down syndrome critical region. Hum Genet 95: 721–722PubMedCrossRefGoogle Scholar
  29. Hongell K, Airaksinen EA (1972) A Gg deletion in a girl with Down’s syndrome. Hum Hered 22: 80–85PubMedCrossRefGoogle Scholar
  30. Huret JL, Delabar JM, Marlhens F, Aurias A, Nicole A, Berthier M, Tanzer J, Sinet PM (1987) Down syndrome with duplication of a region of chromosome 21 containing the CuZn superoxide dismutase gene without detectable karyotypic abnormality. Hum Genet 75: 251–257PubMedCrossRefGoogle Scholar
  31. Ilbery PLT, Lee CWG, Winn SM (1976) Incomplete trisomy in a mongoloid child exhibiting minimal stigmata. Med J Aust 2: 182–184Google Scholar
  32. Jackson JF, North ER 3rd, Thomas JG (1976) Clinical diagnosis of Down syndrome. Clin Genet 9: 483–487PubMedCrossRefGoogle Scholar
  33. Jenkins EC, Duncan CJ, Wright CE, Giordano FM, Wilbur L, Wisniewski K, Sklower SL, French JH, Jones C (1983) Atypical Down syndrome and partial trisomy 21. Clin Genet 24: 9–102Google Scholar
  34. Jeziorowska A, Jakubowsk Li, A Armatys A, Kaluzewski B (1982) Copper/zinc superoxide dismutase (SOD-1) activity in regular trisomy 21, trisomy 21 by translocation and mosaic trisomy 21. Clin Genet 22: 160–164PubMedCrossRefGoogle Scholar
  35. Jeziorowska A, Jakubowsk L, Lach J, Kaluzewski B (1988) Regular trisomy 21 not accompanied by increased copper-zinc superoxide dismutase (SODI) activity. Clin Genet 33: 11–19PubMedCrossRefGoogle Scholar
  36. Kedziora J, Rozynkowa D, Kopff M, Jeske J (1976) Indophenol-oxidase in patients with Down’s syndrome due to simple trisomy and to translocation 21/22. Hum Genet 34: 9–12PubMedCrossRefGoogle Scholar
  37. Kedziora J, Bartorz G, Leyko W, Rozynkawa D (1979) Dismutase activity in translocation trisomy. Lancet i: 105CrossRefGoogle Scholar
  38. Kerem BS, Goitein R, Diamond G, Cedar H, Marcu M (1984) Mapping of DNAase I sensitive regions on mitotic chromosomes. Cell 38: 493–499PubMedCrossRefGoogle Scholar
  39. Kirklionis AJ, Sergovich FR (1986) Down syndrome with apparently normal chromosomes: an update. J Pediat 108: 793–794CrossRefGoogle Scholar
  40. Kitsiou-Tzeli S, Hallett JJ, Atkins L, Latt SA, L B Holmes LB (1984) Familial translocation 4;21 (q2.4;q2.2) leading to unbalanced offspring with partial duplication 4q and 21q without manifestations of the Down syndrome. Am J Med Genet 18: 725–729PubMedCrossRefGoogle Scholar
  41. Korenberg JR, Kawashima H, Pulst S-M, Ikeuchi T, Ogasawara N, Yamamoto K, Schonberg SA, West R, Allen L, Magenis E, Ikawa K, Taniguchi N, Epstein CJ (1990) Molecular definition of a region of chromosome 21 that cause features of the Down syndrome phenotype. Am J Hum Genet 47: 236–246PubMedGoogle Scholar
  42. Korenberg JR, Bradley C, Disteche CM (1992) Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis. Am J Hum Genet 50: 294–302PubMedGoogle Scholar
  43. Korenberg JR, Chen XN, Schipper R, Sun Z, Gonsky R, Gehwehr S, Carpenter N, Daumer C, Dignan P, Disteche C et al (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91: 4997–5001PubMedCrossRefGoogle Scholar
  44. Kurnit DM, Layton WM, Matthysse S (1987) Genetics, chance and morphogenesis. Am J Hum Genet 42: 979–955Google Scholar
  45. Lejeune J, Gautier M, Turpin R (1959) Etude des chromosome somatique des neufs enfants mongoliens. CR Acad Sci Paris 248: 1721–1722Google Scholar
  46. Leonard C, Gautier M, Sinet PM, Selva J, Huret JL (1986) Two Down syndrome patients with rec (21), dup q, inv(21)(p11;q2109) from a familial pericentric inversion.” Ann Genet 29: 181–183PubMedGoogle Scholar
  47. Leschot NJ, Slater RM, Joenje H, Becker-Bloemkolk MJ, Nef JJ (1981) SOD-A and chromosome 21. Conflicting findings in a familial translocation (9p24;21q21.4). Hum Genet 57: 220–223PubMedCrossRefGoogle Scholar
  48. Lewontin RC (1992) Biology as ideology: the doctrine of DNA. Harper, New York, p 26Google Scholar
  49. Linden MG, Bender BG, Robinson A (1995) Sex chromosome tetrasomy and pentasomy. Pediatrics 96: 672–682PubMedGoogle Scholar
  50. Mattei JF, Mattei MG, Baeteman MA, Giraud F (1981) Trisomy 21 for the region 21q22.3: Identification by high resolution R-banding patterns. Hum Genet 56: 409–411PubMedCrossRefGoogle Scholar
  51. McCormick MK, Schinzel A, Petersen M, Stetten G, D Driscoll D, Tranebjaerg L, Mikkelsen M, Watkins P, Antonarkis S (1989) Molecular genetic approach to the characterization of the “Down syndrome region” of chromosome 21. Genomics 5: 325–331PubMedCrossRefGoogle Scholar
  52. Miyazaki K, Yamanaka T, Ogasawara N (1987) A boy with Down’s syndrome having recombinant chromosome 21 but no SOD-1 excess. Clin Genet 32: 383–387PubMedCrossRefGoogle Scholar
  53. Neu RL, Voorhess ML, Gardner LI (1971) A case of 47,XX,(21q-)+ with some stigmata of Down’s syndrome and an IQ of 77. J Med Genet 8: 528–529PubMedCrossRefGoogle Scholar
  54. Niebuhr E (1974) Down’s syndrome — the possibility of a pathogeneic segment on chromosome no. 21. Humangenetik 21: 99–101PubMedCrossRefGoogle Scholar
  55. OMIM (TM) (1995) Online Mendelian Inheritance in Man. The Human Genome Data Base Project, World Wide Web ed. >URL: omimtop.html<. Johns Hopkins University, BaltimoreGoogle Scholar
  56. OMIM (1998) Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 190685: 8/21/98:. World Wide Web URL: Scholar
  57. Paris Conference (1971) Standardization in human genetics, vol 8. Birth defects. Orig Art Ser 1972Google Scholar
  58. Park JP, Wurster-Hill D, Andrews P, Cooley W, Graham J (1987) Free proximal trisomy 21 without the Down syndrome. Clin Genet 32: 342–348PubMedCrossRefGoogle Scholar
  59. Pellissier MC, Laffage M, Philip N, Passage E, Mattei M-G, Mattei J-F (1988) Trisomy 21q223 and Down’s phenotype correlation evidenced by in situ hybridization. Hum Genet 80: 277–281PubMedCrossRefGoogle Scholar
  60. Petersen MB, Tranebjaerg L, McCormick MK, Michelsen N, Mikkelsen M, Antonarakis SE (1990) Clinical, cytogenetic, and molecular characterization of two unrelated patients with different duplications of 21q. Am J Med Genet [Suppl] 7: 104–109Google Scholar
  61. Pfeiffer RA, Kessel EK, Soer K-H (1977) Partial trisomies of chromosome 21 in man. Two new observations due to translocations 19;21 and 4;21. Clin Genet 1: 207–213Google Scholar
  62. Poissonnier M, Saint-Paul B, Dutrillaux B, Chaissaigne M, Gruyer P, de Blignieres-Strouk G (1976) Trisomie 21 partielle (21q21→ q22.2). Ann Genet (Paris) 19: 69–70Google Scholar
  63. Polani PE, Briggs JH, Ford CE, Clarke CM, Berg JM (1960) A mongol child with 46 chromosomes. Lancet i: 721–724CrossRefGoogle Scholar
  64. Priscu R, Sichitui S (1975) Types of enzymatic overdosing in trisomy 21: erythrocytic dismutase-AJ and phosphoglucomutase. Humangenetik 29: 79–83PubMedCrossRefGoogle Scholar
  65. Pueschel SM, Padre-Mendoza T, Ellenbogen R (1980) Partial trisomy 21. Clin Genet 18: 392–395PubMedCrossRefGoogle Scholar
  66. Rahmani Z, Blouin JL, Creau-Goldberg N, Watkins PC, Mattei JF, Poissonnier M, Prieur M, Chettouh Z, Nicole A, Aurias A et al (1989) Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome. Proc Natl Acad Sci USA 86: 5958–5962PubMedCrossRefGoogle Scholar
  67. Rahmani Z, Blouin JL, Creau-Goldberg N, Watkins PC, Mattei JF, Poissonnier M, Prieu M, Chettouh Z, Nicole A, Aurias A et al (1990) Down syndrome critical region around D21S55 on proximal 21q22.3. Am J Med Gyenet 7 [Suppl]: 98–103Google Scholar
  68. Raoul O, Carpentier S, Dutrillaux B, Mallet R, Lejeune J (1976) Trisomies partielles du chromosome 21 par translocation maternelle t (15;21) (q262;q21). Ann Genet Paris 19: 187–190PubMedGoogle Scholar
  69. Sanchez O, Mamunes P, Yunis JJ (1977) Partial trisomy 20 (20q13) and partial trisomy 21 (21pter → 21q21.3). J Med Genet 14: 459–462PubMedCrossRefGoogle Scholar
  70. Shabtai FS (1990) Free proximal trisomy 21 in the mother and malformation syndrome in the son. Am J Med Genet [Suppl] 7: 182–185Google Scholar
  71. Shapiro BL (1975) Amplified developmental instability in Down syndrome. Ann Hum Genet 38: 429–437PubMedCrossRefGoogle Scholar
  72. Shapiro BL (1983) Down syndrome —p a disruption of homeostasis. Am J Med Genet 14: 241–269PubMedCrossRefGoogle Scholar
  73. Shapiro BL (1989) The pathogenesis of aneuploid phenotypes’ the fallacy of explanatory reductionism. Am J Med Genet 33: 146–150PubMedCrossRefGoogle Scholar
  74. Shapiro BL (1994) The environmental basis of the Down syndrome phenotype. Dev Med Child Neurol 36: 84–90PubMedCrossRefGoogle Scholar
  75. Shapiro BL (1997) Whither Down syndrome critical regions? Hum Genet 99: 4211–423CrossRefGoogle Scholar
  76. Sichitui S, Sinet PM, Lejeune J, Frezal J (1974) Surdosage de la forme dimerique de l’indophenoloxydase dans la trisomie 21, secondaire au surdosage genique. Humangenetik 23: 65–72CrossRefGoogle Scholar
  77. Sinet PM, Allard D, Lejeune J, Jerome H (1974) Augmentation d’activite de la superoxide dismutase erythrocytaire dans la trisomie pour le chromosome 21. CR Acad Sci Paris 278: 3267–3270Google Scholar
  78. Sinet PM, LaVelie F, Michelson AM, Jerome H (1975) Superoxide dismutase activities of blood platelets in trisomy 21. Biochem Biophys Res Comm 67: 904–909PubMedCrossRefGoogle Scholar
  79. Sinet P-M, Couturier J, Dutrillaux B, Poissonnier M, Raoul O, Rethore M-O, Allard D, Lejeune J (1976) Trisomie 21 et superoxyde dismutase-1 (IPO-A) — Tentative de localisation sur la sous bande 21q22.1. Exp Cell Res 97: 47–55PubMedCrossRefGoogle Scholar
  80. Smith GF, Berg JM (1976) Down’s anomaly. Churchill Livingstone, EdinburghGoogle Scholar
  81. Summer AT (1994) Functional aspects of the longitudinal differentiation of chromosomes. Eur J Histochem 38: 91–109Google Scholar
  82. Surbt I, Prchlikova H (1970) An extra chromosomal centric fragment in an infant with stigmata of Down’s syndrome. J Med Genet 7: 407–409CrossRefGoogle Scholar
  83. Tan YH, Tischfield J, Ruddle FM (1973) The linkage of genes for the human interferon-induced antiviral protein and indophenol oxidase-B traits to chromosome G-21.” J Exp Med 137: 317–330PubMedCrossRefGoogle Scholar
  84. Taylor AI (1968) Autosomal trisomy sndromes: a detailed study of 27 cases of Edwards syndrome and 27 cases of Patau syndrome. J Med Genet 5: 227–252PubMedCrossRefGoogle Scholar
  85. Thompson MW, McInnes RR, Willard HF (1991) Thompson & Thompson: Genetics in medicine, 5th edn. W. B. Saunders, Philadelphia, pp 240–241Google Scholar
  86. Verma RS, Peakman DC, Robinson A, Lubs HA (1977) Two cases of Down syndrome with unusual de novo translocation. Clin Genet 11: 227–234PubMedCrossRefGoogle Scholar
  87. Vogel F, Motulsky AG (1986) Human genetics: problems and approaches, 2nd edn. Springer, Berlin Heidelberg New York TokyoGoogle Scholar
  88. Wahrman J, Goitein R, Richler C, Goldman B, Ackstein E, Chaki R (1976) The mongoloid phenotype in man is due to trisomy of the distal pale G-band of chromosome 21. In: Pearson PL, Lewis KR (eds) Chromosomes today, vol 5. Halstead Press, New YorkGoogle Scholar
  89. Williams JD, Summitt RL, Martens PR, Kimbrell RA (1975) Familial Down syndrome due to t(10;21) translocation: evidence that the Down syndrome phenotype is related to trisomy of a specific segment of chromosome 21. Am J Hum Genet 27: 478–485PubMedGoogle Scholar
  90. Williams CA, Frias JL, McCormick MK, Antonarakis SE, Cantu ES (1990) Clinical, cytogenetic, and molecular evaluation of a patient with partial trisomy 21 (21q11-q22) lacking the classical Down syndrome phenotype. Am J Med Genet [Suppl] 7:110–114Google Scholar
  91. Wilson GN (1990) Karyotype/phenotype controversy: genetic and molecular implications of alternative hypotheses. Am J Med Genet 36: 500–505PubMedCrossRefGoogle Scholar
  92. Wulfsberg EA, Carrel RE, Klisak IJ, O’Brien TJ, Sykes JA, Sparkes RS (1983) Normal Superoxide dismutase-1 (SOD-1) activity with deletion of chromosome band 21q21 supports localization of SOD-1 locus to 21q22. Hum Genet 64: 271–272PubMedCrossRefGoogle Scholar
  93. Yunis JJ, Kuo MT, Saunders GF (1977) Localization of sequences specifying messenger RNA to light-staining G-bands of human chromosomes. Chromosoma 61: 335–344PubMedCrossRefGoogle Scholar

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© Springer-Verlag Wien 1999

Authors and Affiliations

  • B. L. Shapiro
    • 1
  1. 1.Departments of Oral Science and Laboratory Medicine and Pathology and Institute of Human GeneticsUniversity of MinnesotaMinneapolisUSA

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