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Down Syndrome Abstract
of the Month: Aug 1998

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Ten years of Genomics, chromosome 21, and Down syndrome

Antonarakis SE
Genomics 1998 Jul 1;51(1):1-16

Division of Medical Genetics, University and Cantonal Hospital of Geneva, Geneva

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During the first 10 years of the journal Genomics (1987-1997), the molecular structure of human chromosome 21 (HC21) has been intensively investigated. Due to its small size and involvement in Down syndrome, it continues to serve as a model in the development of "genomics technologies." Increasingly more detailed genetic, radiation hybrid, physical, and transcription maps, in addition to NotI restriction and chromosomal breakpoint maps, of HC21 have been developed, and approximately 10% of its genes have been cloned. These maps have been vital in the localization of loci for 15 monogenic disorders to HC21, and 10 of these genes have been identified and characterized. The genetic maps have aided in the detailed elucidation of the origin of the supernumerary HC21 in trisomy 21 from investigations of recombination and nondisjunction events. Mouse models of Down syndrome, with partial trisomy 16, the mouse chromosome principally syntenic to HC21, have been created and initially characterized. A substantial number of the above studies related to the molecular mapping, gene cloning, and infrastructure of HC21 were published in Genomics (e.g., approximately 30% of papers describing HC21 maps were published here). The future goals of genomic analysis of HC21 will be the determination of its complete nucleotide sequence and the identification and functional analysis of all of its genes. These advances will help to provide a molecular explanation of the pathophysiology of Down syndrome and aid in the identification of genes for monogenic and polygenic disorders that map on this chromosome. Novel therapeutic interventions for Down syndrome and the monogenic and polygenic disorders that map to HC21 will be designed and tried based on the knowledge of the disease pathogenesis resulting from the genomic analysis.

My comments:

An excellent summary of where we are and how far we've come over the last 10 years. There is also a summary of what we know about the origin of the third chromosome, in 'free" trisomy 21 as well as translocations.

Some specific points from the article:

There are now 86 genes identified on HC21, approximately 12% of the total chromosome. There are an additional 55 genes partially identified.

The DS "critical region," while not necessarily the only genes on the HC21 affecting the DS phenotype, is almost completely indexed.

The author states: "To date, there is no convincing functional link between the overexpression of any of the known genes on HC21 with the various phenotypes that constitute Down syndrome."

From another section: "In the next 5 years of HC21/DS research, we expect that all the transcription units of HC21 will be identified and the entire sequence of 21q will be determined....Functional analysis of these genes will be the focus of many laboratories. The involvement of some genes in the development of Down syndrome phenotypes will be elucidated."

And from the summary, lest anyone get too optimistic: "It will be a difficult task to identify which genes are involved in the pathophysiology of DS. Further, as there are many allelic variants of genes, it may be that only the presence of a certain combination of three alleles for some HC21 genes may result in a certain phenotype....the genetic background of the individual with trisomy 21 may also affect the phenotype."

(By the way, an allele is a "flavor" of gene. For instance, the gene controlling eye color has an allele for blue, one for green, etc. You only have one allele for the gene. "Phenotype" means physical characteristics of the individual.)
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