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Initially, the view that all aspects of a phenotype, and hence all manifestations of a mendelian syndrome, derive from a single function (or dysfunction) of a mutant allele gained ascendancy. Support for the importance of pleiotropy gradually diminished, and reached a low point in the 1940s with the one gene\u2010one enzyme hypothesis. Studies of mammals and humans with heritable disorders of connective tissue sustained the notion that \u201cgenuine\u201d pleiotropy probably did not exist. However, the demise of the relevance of pleiotropy was premature. Detailed understanding of gene organization, expression, and mutation indicates several mechanisms, such as multifunctional proteins, alternative splicing of messenger RNA, and overlapping coding sequences, through which genuine pleiotropy likely occurs in normal development and function, in mendelian syndromes, and in conditions due to somatic mutation. Furthermore, a broad definition of pleiotropy is warranted to subsume syndromes caused by abnormal function of contiguous genes, such as through large deletions, mutation of regulatory elements that coordinate expression, or less clearly understood \u201cposition effects.\u201d Thus, the use of pleiotropy in the context of aneuploidy syndromes is not inappropriate.<\/jats:p>","DOI":"10.1002\/ajmg.1320340120","type":"journal-article","created":{"date-parts":[[2005,6,11]],"date-time":"2005-06-11T13:27:54Z","timestamp":1118496474000},"page":"124-134","source":"Crossref","is-referenced-by-count":33,"title":["Pleiotropy revisited: Molecular explanations of a classic concept"],"prefix":"10.1002","volume":"34","author":[{"given":"Reed E.","family":"Pyeritz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,6,3]]},"reference":[{"key":"e_1_2_1_2_1","first-page":"1","article-title":"Les formes fruste du syndrome dolichost\u00e9nom\u00e9lique de Marfan","volume":"26","author":"Apert E","year":"1938","journal-title":"Nourisson"},{"key":"e_1_2_1_3_1","first-page":"309","article-title":"Congenital aneurysmal dilatation of aorta associated with arachnodactyly","volume":"72","author":"Baer RW","year":"1943","journal-title":"Bull Johns Hopkins Hosp"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.27.11.499"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320290316"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.52.4.651"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320190111"},{"key":"e_1_2_1_8_1","first-page":"273","article-title":"A final word on the tricho\u2010rhino\u2010phalangeal syndromes","volume":"31","author":"B\u00fchler EM","year":"1987","journal-title":"Am J Med Genet"},{"key":"e_1_2_1_9_1","doi-asserted-by":"crossref","unstructured":"ByersP(1989):Inherited disorders of collagen gene structure and expression. 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