Less than half of the newborn and early childhood referrals for cytogenetic analysis have a chromosomal abnormality as an explanation for their phenotype. Some of the rest can be explained by gene-specific effects or can be attributed to teratogenic exposure during development, but about half are of unknown etiology. A number of he­reditary diseases, usually associated with a high incidence of cancer or premature aging, are characterized by inher­ent genomic instability at the chromosomal level, at the base pair (bp) level, or both. We wished to determine whether such genetic instability, manifested as spontane­ous hypermutability, might be found in a population of pediatric patients referred for cytogenetic analysis who had no chromosomal abnormalities.

The glycophorin A (GPA) somatic mutation assay is based on loss of expression of one allele of a heterozygous pair at the autosomal locus determining the human MN blood group [1]. It has been used extensively to detect and quantify the effects of genotoxic exposure in humans [2,3], including exposures in utero [4,5] and in childhood [6-9]. It has also been used to demonstrate high levels of sponta­neous hypermutability in several hereditary diseases asso­ciated with deficiency of DNA repair, including ataxia telangiectasia (AT) [10,11], Fanconi’s anemia (FA) [12], Bloom’s syndrome (BS) [13,14] and Werner’s syndrome (WS) [15,16]. We have recently shown that the high spon­taneous mutation frequencies (M_f) revealed by the GPA assay are diagnostic for AT and FA [17,18].