Visible cytogenetic abnormalities are detected in approximately 10-20 percent of children with mild to severe mental retardation (including autism) and approximately 2-5 percent of couples with recurrent pregnancy loss. As current cytogenetic banding resolution only detects imbalances greater than 2 million basepairs of DNA, it is likely that submicroscopic abnormalities affecting the ends of chromosomes, the telomeres, may play a role in a significant proportion of unexplained (""""""""idiopathic"""""""") mental retardation and pregnancy loss. The hypothesis to be tested is that submicroscopic gene dosage imbalances at human telomeres contribute significantly and disproportionately to idiopathic mental retardation and recurrent pregnancy loss. Special features of human telomeres which suggest they may be disproportionately represented compared to other regions of the genome include the fact that telomeres are the most gene rich regions of the human genome, and therefore very small imbalances are likely to have significant genetic consequences. Aspects of telomere structure and polymorphism may mediate nonhomologous chromosome pairing and unequal cross-over events leading to gene dosage imbalance. Studies to address these hypotheses only recently have become possible due to development of a complete set of specific human telomere probes. Of 41 human telomeres, unique probes within 300 kb of the end of the chromosome are available for 40. This probe set provides an entree into more detailed biological studies of the architecture of human telomeres, as well as the frequency, mechanisms, and consequences of telomeric rearrangements in idiopathic mental retardation, autism, pregnancy loss, birth defects and cancer.
Specific aims are: (1) Molecular characterization of polymorphism and recent evolutionary duplications/rearrangements of subtelomeric transition zones by analysis of human populations and nonhuman primates, (2) Determination of the frequency and pattern of cryptic deletions and translocations in unexplained mental retardation/autism probands with a family history suggestive of chromosomal translocation, and (3) Determination of the mechanisms and consequences of telomere imbalance by detailed molecular analysis of the size of the imbalance, breakpoints, gene/EST content, and parental origin.
