No abstract

Here we report on studies of the reproductive risks for heterozygous carriers of chromosome translocations. Pregnancy outcome, breakpoints, mode of segregation of the translocated chromosomes, and resulting chromosome imbalance were analyzed in 58 families (46 with reciprocal and 12 with Robertsonian translocations) ascertained for birth of a malformed child, recurrent spontaneous abortion, or hypogonadism. These families include a total of 122 informative sibships. The analysis of the data, after correction for ascertainment bias, showed that the incidence of spontaneous abortion is nearly 50% in reciprocal and between 20 and 25% in Robertsonian translocation families ascertained for malformed child or recurrent abortion. The risk of malformed infants with unbalanced genome is approximately 6% among the liveborn offspring of reciprocal translocation carriers and 23% among the liveborn offspring of carrier mothers of t(14q21q). The distribution of the breakpoints on the chromosomes involved in reciprocal translocations ascertained through a malformed child is nonrandom, with an excess on chromosomes 5, 9, 13, and 15. The study of chromosome imbalance, expressed as gain or loss of a portion of genetic information relative to the total haploid autosome length (percent HAL), shows that among the common types of disjunction-segregation leading to unbalanced gametes, adjacent 1 seems to be the one producing on the average the least level of genome imbalance. This explains why it is the most frequently observed type of segregation giving rise to gametes from which subjects with a chromosome imbalance compatible with life can be generated.

The incidence of Down syndrome (DS) families where one of the parents is an heterozygous carrier of pericentric inversion of the heterochromatic region of chromosome 9 -inv (9) (qh) -was determined in 3 independent groups of 100 families each. The total number of 17 such families found in the sample is significantly greater than the expected number of 5.73 for a sample of non-DS families of equal size. Consequently, the statistical association of the presence of inv (9) (qh) in one parent with the birth of a DS offspring, and the correlative 3-fold increased risk of a DS child for such families, seem to be demonstrated. A study of the origin of nondisjunction, using restriction fragment length polymorphism (RFLP) segregation analysis with a sufficient number of chromosome 21 specific probes, has provided complete information in 7 of 8 available families. Although the statistical interpretation of the results is not straightforward, due to the small size of the sample, the observed data do not contradict the assumption that the presence of inv (9) (qh) in a parent increases, by a factor of about 3, the chance that the offspring will inherit an extra chromosome 21 from that parent. Nevertheless, gathering further data appears desirable because stronger evidence would have relevance both for clinical implications and for the understanding of the function of heterochromatin, particularly with respect to meiotic and mitotic processes.

These results indicate that the DNA-damaging effect of BLM is amplified by GH and, more markedly, IGF-I and -II. IGF-I and -II also stimulate p53 protein expression that, taking part in DNA repair, may counteract the IGF action on genome stability.

Chromosomal fragile sites that are inducible by methotrexate and aphidicolin are frequent in the human population. To assess the frequency and distribution of these common fragile sites, we performed a cytogenetic survey on lymphocytes from subjects known to be particularly prone to breakage because of constitutional chromosomal instability, the possession of a rare fragile site, or Fanconi anemia. Furthermore, a group of cancer patients was included in this study in view of possible acquired chromosomal instability. Lymphocyte chromosomes from several healthy donors were analyzed under identical conditions. We found that methotrexate- and aphidicolin-induced fragile sites are widespread in the general population, showing a similar breakpoint distribution. Ten fragile sites (3p14, 16q23, 2q32, 6q25, 4p16, 4q31, 14q24, 1p31, 20p12, 7q21) were observed in at least 40% of the individuals among the different groups. Our data point out a significantly increased breakage induced by aphidicolin in lymphocytes from cancer patients and, to a lesser extent, from rare fragile sites carriers. These results suggest that common fragile sites are enhanced in some constitutional and acquired conditions.