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1.1 Trisomy 21 causes phenotypes associated with Down syndrome Down syndrome (DS) occurs in approximately 1 out of 700 live births and most commonly results from three copies of human chromosome 21 (Hsa21) (Christianson, 2006). DS is a multifaceted disorder with over 80 clinically defined phenotypes including those affecting the central nervous system, heart, gastrointestinal tract, skeleton and immune system (Epstein, 2001; Van Cleve and Cohen, 2006). Phenotypes associated with individuals with DS vary in both incidence and severity, leading to a vast array of phenotypic combinations among those with Trisomy 21 (Ts21) (Deutsch et al., 2005; Epstein, 2001; Van Cleve et al., 2006; Van Cleve and Cohen, 2006). For example, cognitive impairment, hypotonia and craniofacial features are universal phenotypes, whereas cardiac abnormalities only affect approximately half of individuals with DS. Individual phenotypes similar to those seen in DS have been documented in individuals without Ts21, but a general higher incidence and severity of these phenotypes in individuals with DS suggests that trisomy plays an important role in initiating or modifying these features (Epstein, 2001; Roper and Reeves, 2006). Although it has been suggested that common mechanisms may be involved in similar phenotypes seen in individuals with and without Ts21, common pathophysiology must be proven for each individual phenotype. A chromosomal basis for DS was postulated as early as 1932 (Patterson and Costa, 2005). After Jerome Lejeune established that DS was caused by an extra Hsa21, he studied the metabolic pathways associated with Ts21 phenotypes in an attempt to cure DS (Neri and Opitz, 2009). Alternate causes of DS, including translocations and mosaicism of extra material from Hsa21, were established shortly after the chromosomal basis of DS had been discovered (Patterson and Costa, 2005). These early genetic findings set the stage for current paradigms and research surrounding the gene-phenotype relationships in DS. Although ~95% of the incidence of DS is due to trisomy of the entire Hsa21, DS also results from extra genetic material from Hsa21 translocated to other chromosomes. Additionally, some individuals with DS phenotypes have Ts21 in only a portion of their cells (mosaicism). Differences in genetic and cellular composition of the trisomy may lead to the observed differences in DS phenotypic incidence and severity. Genotypic and phenotypic variations have also been used to hypothesize about trisomic genes or chromosomal regions that may cause or significantly alter DS phenotypes. Such genotype-phenotype correlations are important in defining the etiology of traits associated with DS as well as suggesting possible therapeutic mechanisms to overcome deficits seen in individuals with DS.

Down Syndrome: A Complex and Interactive Genetic Disorder