Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and an AMzelmer-like dementia. Moreover, DS is a model for the study of human aneuploldy. Although With the discovery that DS was caused by trisomy 21 (3, 4), and the subsequent proposal that chromosome 21 band q22 was "pathogenetic" for DS (5), the foundation was laid for elucidating the fundamental biochemical and morphogenetic pathways of abnormal development in this aneuploidy. There followed a series ofreports ofindividuals with "partial trisomy 21" (for review, see ref. 6) that appeared to indicate that regions might be defined that were likely to contain genes responsible for particular features of DS. These studies provide the basis for construction of a DS phenotypic map.By "phenotype" we mean a measurable parameter and include clinical, physical, cellular, and physiological components. By "phenotypic mapping" we mean the molecular definition of a physical region that is likely to contain the gene(s) whose overexpression is ultimately responsible in part for the phenotype. The current revolution in human molecular genetics and the development of a physical map of chromosome 21 now provide the possibility to understand the genetic basis for some of these defects and, therefore, to provide a necessary first step for their prevention, amelioration, and perhaps ultimately, their treatment.Phenotypic maps provide the basis for clinical prognosis for individuals with partial aneuploidy for chromosome 21, and when of high resolution, the basis for the identification of the genes responsible for the phenotypes. One approach to this combines the phenotypic information from individuals with "partial trisomy" such as those described above with a molecular definition of their duplicated chromosomal regions. Once the molecular markers for a region are defined, the genes within it may then be identified, characterized, and ultimately tested for their relationship to a given phenotype. This report describes the molecular and phenotypic definition of these individuals, provides a theoretical framework, and utilizes this to construct a molecular "map" of the phenotypes associated with DS.

Down syndrome is usually caused by complete trisomy 21. Rarely, it is due to partial trisomy of the segment 21q22. We report on a 33-month-old girl with tetrasomy 21 pter-->q22.1 resulting from an extra chromosome idic(21)(q22.1). She has craniofacial traits typical of Down syndrome, including brachycephaly, third fontanel, upward slanting palpebral fissures, round face, and protruding tongue. Speech development is quite delayed whereas motor development is only mildly retarded. The molecular content of the extra isodicentric chromosome was defined by molecular genetic investigations using 13 single copy probes unique to chromosome 21, and SOD1 expression studies. The child was found to have 4 copies of the region defined by D21S16 (21cen) through D21S93 on 21q22.1 and two copies of the remaining region defined by SOD1-->D21S55-->D21S123. In view of the recent assignment of Down syndrome facial characters to the 21q22 region, defined in part by D21S55, it is significant that this child shows a subset of Down syndrome facial manifestations, without duplication of this region. These results suggest that genes contributing to the facial and some of the hand manifestations of Down syndrome also exist in the chromosomal region proximal to D21S55 in band 21q22.1.