Few reliable data exist concerning the recurrence risk for individual trisomies or the risk for recurrence of trisomy for a different chromosome. We collected records from two sources: (1) prenatal diagnoses performed at the Hopital Sainte-Justine in Montreal and (2) karyotype analyses performed at Genzyme. Using the standardized morbidity ratio (SMR), we compared the observed number of trisomies at prenatal diagnosis with the expected numbers, given maternal age–specific rates (by single year). SMRs were calculated both for recurrence of the same trisomy (homotrisomy) and of a different trisomy (heterotrisomy). After all cases with an index trisomy 21 were combined, the SMR for homotrisomy was 2.4 (90% CI 1.6–3.4; P = .0005). For women with both the index trisomy and subsequent prenatal diagnosis at age

https://www.cell.com/ajhg/pdf/S0002-9297(07)63310-2.pdf

Trisomy Recurrence: A Reconsideration Based on North American Data

Trisomy in humans: incidence, origin and etiology

Chromosomal aneuploidy is a fundamental characteristic of the human species. In this review we summarize the knowledge about the origin and mechanisms of nondisjunction in human trisomy 21 that has accumulated during the last decade by using DNA polymorphism analysis. The first molecular correlate of nondisjunction in humans is altered recombination, meiosis I errors being associated with reduced recombination and maternal meiosis II errors with increased recombination between the nondisjoined chromosomes. Thus, virtually all maternal meiotic errors of chromosome 21 seem to be initiated in meiosis I. Advanced maternal age remains the only well documented risk factor for maternal meiotic nondisjunction, but there is, however, still a surprising lack of understanding of the basic mechanisms behind the maternal age effect.

Nondisjunction in trisomy 21: origin and mechanisms.

The scientific community is developing a compelling body of evidence that shows the importance of the in utero environment (including chemical and hormonal levels) to the ultimate health of the child and even of the aging adult. This article summarizes the evidence that shows this impact begins with conception. Only a full life-cycle evaluation will help us understand these impacts, and only such an understanding will produce logically prioritized mitigation strategies to address the greatest threats first. Clearly, the time for analysis begins when the next generation is but a twinkle in the eye.

Off to a good start: the influence of pre- and periconceptional exposures, parental fertility, and nutrition on children's health.

In order to investigate the mechanism(s) underlying mosaicism for trisomy 21, we genotyped 17 families with mosaic trisomy 21 probands, using 28 PCR-detectable DNA polymorphic markers that map in the pericentromeric region and long arm of chromosome 21. The percentage of cells with trisomy 21 in the probands' blood lymphocytes was 6%-94%. There were two classes of autoradiographic results: In class I, a "third allele" of lower intensity was detected in the proband's DNA for at least two chromosome 21 markers. The interpretation of this result was that the proband had inherited three chromosomes 21 after meiotic nondisjunction (NDJ) (trisomy 21 zygote) and subsequently lost one because of mitotic (somatic) error, the lost chromosome 21 being that with the lowest-intensity polymorphic allele. The parental origin and the meiotic stage of NDJ could also be determined. In class II, a "third allele" was never detected. In these cases, the mosaicism probably occurred either by a postzygotic, mitotic error in a normal zygote that followed a normal meiosis (class IIA mechanism); by premeiotic, mitotic NDJ yielding an aneusomic zygote after meiosis, and subsequent mitotic loss (class IIB mechanism); or by a meiosis II error with lack of crossover in the preceding meiosis I, followed by mitotic loss after fertilization (class IIC mechanism). Among class II mechanisms, the most likely is mechanism IIA, while IIC is the least likely. There were 10 cases of class I and 7 cases of class II results.(ABSTRACT TRUNCATED AT 250 WORDS)

Understanding the mechanism(s) of mosaic trisomy 21 by using DNA polymorphism analysis

We used DNA polymorphic markers on the long arm of human chromosome 21 in order to determine the parental and meiotic origin of the extra chromosome 21 in families with recurrent free trisomy 21. A total of 22 families were studied, 13 in which the individuals with trisomy 21 were siblings (category 1), four families in which the individuals with trisomy 21 were second-degree relatives (category 2), and five families in which the individuals with trisomy 21 were third-degree relatives, that is, their parents were siblings (category 3). In five category 1 families, parental mosaicism was detected, while in the remaining eight families, the origin of nondisjunction was maternal. In two of the four families of category 2 the nondisjunctions originated in individuals who were related. In only one of five category 3 families, the nondisjunctions originated in related individuals. These results suggest that parental mosaicism is an important etiologic factor in recurrent free trisomy 21 (5 of 22 families) and that chance alone can explain the recurrent trisomy 21 in many of the remaining families (14 of 22 families). However, in a small number of families (3 of 22), a familial predisposing factor or undetected mosaicism cannot be excluded.

Francoise Serville

Papers

DNA polymorphism analysis in families with recurrence of free trisomy 21.