{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:13:24Z","timestamp":1789647204736,"version":"4.0.0"},"reference-count":39,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2009,11,17]],"date-time":"2009-11-17T00:00:00Z","timestamp":1258416000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Over the past some 160 years, the study of Down syndrome (DS) went from early efforts of differentiating it from cretinism (S\u00e9guin) to its establishment as a specific nosologic category of mental deficiency (Down) and subsequent attempts to infer its cause. DS was known to be an overwhelmingly sporadic disorder, concordant in MZ and discordant in DZ twins and associated with increased maternal reproductive age (Penrose). Beginning in the 1920s and based in part on phenotype analysis and early cytogenetic insights in <jats:italic>Drosophilia<\/jats:italic>, several clinicians (Halbertsma, Waardenburg, Bleyer, Fanconi) and the geneticist C.B. Davenport postulated that DS might be due to a chromosome abnormality; only Davenport, with T.S. Painter, made an actual attempt to perform a clinical\/cytological study (with inconclusive results). It was only with the application of the methods of Belling (colchicine, squash preparations) and of T.C. Hsu (hypotonic solution) to PHA\u2010treated cell cultures in the mid\u2010late 1950s, that it became possible to study, accurately, the human karyotype and its aberrations, allowing Lejeune et al. and Jacobs et al. in 1959 to discover the cause of DS. Nowadays, aided with powerful molecular methods, it has become possible to attain insights into the pathogenesis of DS based on the study of many duplications\/deficiencies of HSA21 in humans and ingeniously constructed cytogenetic rearrangements of MMA16 in the mouse. These suggest a complex epigenetic interaction between genes on HSA21 and many (?most) other genes in the human genome, akin to an attempt at speciation as suggested early during the last century by Blakesly in his work on <jats:italic>Datura<\/jats:italic>. Many important ongoing efforts are underway in several countries to understand the developmental biology of DS, offering hope of ultimate amelioration for those averse to pregnancy termination. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.33138","type":"journal-article","created":{"date-parts":[[2009,11,17]],"date-time":"2009-11-17T19:38:43Z","timestamp":1258486723000},"page":"2647-2654","source":"Crossref","is-referenced-by-count":27,"title":["Down syndrome: Comments and reflections on the 50th anniversary of Lejeune's discovery"],"prefix":"10.1002","volume":"149A","author":[{"given":"Giovanni","family":"Neri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Opitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,11,17]]},"reference":[{"key":"e_1_2_6_2_1","unstructured":"Excellent historical bibliographies are in Zellweger [1965] Vollman [1969] and Penrose and Smith [1966]."},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000291570.63450.44"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1448"},{"key":"e_1_2_6_5_1","first-page":"86","volume-title":"The genus Datura","author":"Avery AG","year":"1959"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/279845"},{"key":"e_1_2_6_7_1","unstructured":"BlakesleeAF.1930.Extra chromosomes a source of variations in the Jimson weed. Ann Report Smithsonian Inst (Publication 3077). pp. 431\u2013450."},{"key":"e_1_2_6_8_1","first-page":"342","article-title":"Indications that mongoloid imbecility is a gametic mutation of degressive type","volume":"47","author":"Bleyer A","year":"1934","journal-title":"Am J Dis Child"},{"key":"e_1_2_6_9_1","first-page":"222","article-title":"Theoretical and clinical aspects of mongolism","volume":"34","author":"Bleyer A","year":"1937","journal-title":"J Mo Med Assoc"},{"key":"e_1_2_6_10_1","unstructured":"BrainWR(Lord).1967.Chairman's opening remarks. In Wolstenhome GEW Porter R editors. Mongolism. Ciba Foundation Study Group No. 25. Boston Little Brown Co. pp. 1\u20135 (with biographical data on John Langdon Haydon Down 1828\u20101896. John's son Dr. Reginald Down was Lord Brain's father\u2010in\u2010law)."},{"key":"e_1_2_6_11_1","unstructured":"DavenportCB.1932.Mendelism in man. Proc VI Int Congr Genet: 135\u2013140."},{"key":"e_1_2_6_12_1","first-page":"259","article-title":"Observations of an ethnic classification of idiots","volume":"3","author":"Down JLH","year":"1866","journal-title":"Lond Hosp Clin Lect Rep"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320370706"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1086\/338915"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808319105"},{"key":"e_1_2_6_16_1","first-page":"995","article-title":"Die Mutationstheorie des Mongolismus (M.)","volume":"69","author":"Fanconi G","year":"1939","journal-title":"Schweiz Med Wschr"},{"key":"e_1_2_6_17_1","first-page":"285","article-title":"Pr\u00e4natale Pathologie","volume":"91","author":"Fanconi G","year":"1961","journal-title":"Schweiz Med Wschr"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4612-6159-9"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(59)91892-6"},{"key":"e_1_2_6_20_1","volume-title":"Evolution and specification: Essays in honor of M.J.D. White","author":"John B","year":"1981"},{"key":"e_1_2_6_21_1","volume-title":"A history of the care and study of the mentally retarded","author":"Kanner L","year":"1964"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813248106"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.11.4997"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-68006-9_8"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320370705"},{"key":"e_1_2_6_26_1","first-page":"1721","article-title":"\u00c9tude des chromosomes somatiques de neuf enfants mongoliens","volume":"248","author":"Lejeune J","year":"1959","journal-title":"CR Acad Sci"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098992"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320370707"},{"key":"e_1_2_6_29_1","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1192\/bjp.85.359.1141","article-title":"Maternal age, order of birth and developmental abnormalities","volume":"85","author":"Penrose LS","year":"1939","journal-title":"J Ment Sci"},{"key":"e_1_2_6_30_1","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1192\/bjp.97.409.738","article-title":"Maternal age in familial mongolism","volume":"97","author":"Penrose LS","year":"1951","journal-title":"J Ment Sci"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1954.tb36424.x"},{"key":"e_1_2_6_32_1","volume-title":"Down's anomaly","author":"Penrose LS","year":"1966"},{"key":"e_1_2_6_33_1","doi-asserted-by":"crossref","unstructured":"RasmussenSA WhiteheadN CollierSA Fr\u00edasJL.2008.Setting a public health research agenda for Down syndrome: Summary of a meeting sponsored by the Centers for Disease Control and Prevention and the National Down Syndrome Society. 146A: 2998\u20133010.","DOI":"10.1002\/ajmg.a.32581"},{"key":"e_1_2_6_34_1","first-page":"220","volume-title":"The genus Datura","author":"Satina S","year":"1959"},{"key":"e_1_2_6_35_1","volume-title":"Le traitement moral, l'hygi\u00e8ne et l'\u00e9ducation des idiots et des autres enfants arri\u00e8res","author":"S\u00e9guin E","year":"1846"},{"key":"e_1_2_6_36_1","volume-title":"Idiocy and its treatment by the physiological method","author":"S\u00e9guin E","year":"1866"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320140206"},{"key":"e_1_2_6_38_1","unstructured":"VollmanRF.1969.Down's syndrome (mongolism) a reference bibliography. 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