The chromosome-16 and the X-chromosome forms of alpha-thalassemia--ATR-16 and 
ATR-X--exemplify 2 important causes of syndromal mental retardation. ATR-16 is a 
contiguous gene syndrome which arises from loss of DNA from the tip of 
chromosome 16p13.3 by truncation, interstitial deletion, or unbalanced 
translocation. It provided the first example of a chromosome translocation that 
could be detected by molecular analysis but not conventional cytogenetics. It 
also provided the first example of a telomeric truncation giving rise to a 
complex genetic syndrome. In contrast ATR-X appears to be due to mutations in a 
trans-acting factor that regulates gene expression. Mutations in transcription 
factors have recently been identified in a number of genetic diseases (for 
example, Denys-Drash syndrome, WT1 [19]; pituitary dwarfism, PIT1 [16]; 
Rubinstein-Taybi syndrome, CBP [20]. Not only is this mechanism proving to be an 
important cause of complex syndromes but it is providing new perspectives on 
certain developmental pathways. XH2 may not be a classical transcription factor 
but it is certainly involved in the regulation of gene expression, exerting its 
effects on several different genes. It seems likely that other mutations in this 
class of regulatory proteins will be found in patients with complex disorders 
including mental retardation. In broader terms the 2 mechanisms described here 
may prove to be responsible for a significant proportion of mental retardation. 
However, without a feature such as alpha-thalassemia to pinpoint the area of 
genome or pathways involved it may prove difficult to identify other, similarly 
affected genes underlying other forms of mental retardation. As the human genome 
project and rapid genome analysis evolve this problem should become less of an 
obstacle. In the meantime, it is very worthwhile to continue looking for unusual 
clinical associations that may point to critical genes underlying human genetic 
disorders.