A DEFECT OF DNA repair is the factor underlying the chromosome instability syndromes, also known as chromosome breakage syndromes (Brewer et al., 1997; Michelson and Weinert, 2000; Taylor, 2001). The “instability” refers to the predisposition of the chromosomes to undergo rearrangement or to display other abnormal cytogenetic behavior. Their inclusion in this book is warranted in that special cytogenetic techniques may have a role in clinical diagnosis and prenatal diagnosis, albeit that direct molecular analysis is having an increasing role, as more is learned of the mutational basis of...

A DEFECT OF DNA repair is the factor underlying the chromosome instability syndromes, also known as chromosome breakage syndromes (Brewer et al., 1997; Michelson and Weinert, 2000; Taylor, 2001). The “instability” refers to the predisposition of the chromosomes to undergo rearrangement or to display other abnormal cytogenetic behavior. Their inclusion in this book is warranted in that special cytogenetic techniques may have a role in clinical diagnosis and prenatal diagnosis, albeit that direct molecular analysis is having an increasing role, as more is learned of the mutational basis of these syndromes.

The classic chromosome instability syndromes are Fanconi pancytopenia syndrome, Bloom syndrome, and ataxia-telangiectasia. The main cytogenetic features are listed in Table 21–1. They are mendelian conditions, and in each the mode of inheritance is autosomal recessive. There is genetic heterogeneity in Fanconi syndrome, with cells homozygous for one mutation able to correct in vitro cells homozygous for another mutation (“complementation”). We briefly note three other rare mutagen-hypersensitivity syndromes—the Nijmegen breakage syndrome; the immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome; and Seckel syndrome. Proneness to cancer is a common concomitant of several of the breakage syndromes (Duker, 2002). Some of these genes have in common their interaction with the breast cancer susceptibility gene BRCA1, their protein products forming a “BRCA1-associated genome surveillance complex” (Futaki and Liu, 2001).

Rare or even unique families with various clinical presentations have been associated with chromosomal instability, and some representatives are mentioned in this chapter. Chromosome instability has been reported as an occasional observation in quite a number of known conditions. This list includes, among others, the Cockayne/cerebro-oculo-facial-skeletal syndrome spectrum, xeroderma pigmentosum, Rothmund-Thomson syndrome, Dubowitz syndrome, and Riyadh chromosome breakage syndrome. But in several the associations are not clear, the relevance for genetic counseling is uncertain (other than in supporting a diagnosis), and we do not consider them here. Likewise, chromosome instability is a feature of many cancers, and it may indeed be a crucial factor in the process of carcinogenesis; but this a somatically acquired attribute, and not of relevance in the present context.

A different cytogenetic observation is that of premature sister chromatid separation. This is a feature of Roberts syndrome, Cornelia de Lange syndrome, variegated aneuploidy syndrome, and Warsaw breakage syndrome, and we make brief mention of these conditions. The genes underlying these disorders code for cohesins, which contribute to the control of sister chromatid segregation at cell division, and thus are dubbed “cohesinopathies.”