In humans, de novo (presumed mutant) chromosomal rearrangements, whether balanced or unbalanced, occur in 2/1000 live births. This estimate is based on 63,000 fetal amniocenteses, which were diagnosed in the New York State Chromosome Registry (Hook & Cross, 1987). Of these, about 0.5 per 1000 are de novo markers; about 0.5 per 1000 other de novo unbalanced translocations and about 1.0 per 1000 de novo balanced rearrangements. The rate of inherited rearrangements was about 2.9 per 1000, including 0.3 per 1000 inherited markers, 0.2 per 1000 other inherited unbalanced rearrangements, and about 2.4 per 1000 inherited balanced abnormalities. Among fetuses studied because of maternal exposure to putative mutagens, there was an excess of mutants, 2.9-5.7 per 1000 versus 1.7-2.2 per 1000 (Hook & Cross, 1987). These findings suggest that workplace or environmental exposures may increase risk of structural cy-togenetic abnormalities in the fetus that, in turn, may be associated with birth defects and neurodevelopmental delay in the infant.
Warburton (1984, 1987, 1991) reported the results of a 10-year collection of data from a series of over 377,000 amniocenteses in which the occurrence rate of de novo balanced reciprocal translocations, Robertso-nian translocations, and inversions was estimated to be about 1 per 1000. The most common de novo balanced chromosomal anomalies were de novo reciprocal translocations (1 per 2000). The overall risk of a serious congenital anomaly, including but not limited to MR, for balanced reciprocal translocations and inversions was 6.7% (95% CI 3.1-10.3%). In this same study, de novo supernumerary markers were found in 1 in 2500 amniocenteses, and had a risk of approximately 15% of being associated with an abnormal fetal outcome. De novo unbalanced rearrangements, including supernumerary small markers, have been estimated to occur in about 1 in 1000 amniocenteses which were carried out for reasons other than suspected fetal anomalies (Hook & Cross, 1987). This rate increased to 1.8 per 1000 when amniocentesis was performed because of known or suspected fetal pathology.
However, these rates are based on cytogenetic methods that may miss small deletions or translocations and underestimate the impact of chromosomal anomalies on neurodevelopmental disorders. There is mounting evidence that chromosomal rearrangements involving the subtelomeric regions of chromosomes contribute to moderate to severe MR and are associated with dysmorphic phenotypic features (Flint et al., 1995; Knight et al., 1999). Flint and his colleagues (Knight et al., 1999) reported that subtelomeric abnormalities, requiring microassays or FISH to be detected, occurred in 7.4% (95% CI 4.4-10.4) of 284 children with previously unexplained moderate to severe MR. About half of the subtelomeric rearrangement cases were familial and the other half were isolated, apparently de novo cases. Approximately 10% of the de novo rearrangements had abnormal outcomes. In both the familial and de novo groups approximately 60% of the chromosomal anomalies were paternal and 40% were maternal in origin. If cases are selected to include dysmorphic features as well as developmental delay, chromosomal aberrations may be found in as many as 13.0% (Popp et al., 2002). On the other hand, van Karnebeek et al. (2002) screened 266 children in a consecutive cohort of cases with unexplained MR presenting to an academic tertiary center for diagnosis and found that the total frequency of cytogenetic anomalies was 10%, but the frequency of subtelomeric rearrangements was low (0.5%, van Karnebeek et al., 2002). Thus, screening for subtelomeric rearrangements is likely to be most effective when combined with targeted selection criteria, including unexplained MR, dysmorphic features, and a positive family history with two or more affected individuals (Popp et al., 2002).
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