UNDERSTANDING THE MECHANISM(S) OF MOSAIC TRISOMY-21 BY USING DNA POLYMORPHISM ANALYSIS

In order to investigate the mechanism(s) underlying mosaicism for tris omy 21, we genotyped 17 families with mosaic trisomy 21 probands, usin g 28 PCR-detectable DNA polymorphic markers that map in the pericentro meric region and Long arm of chromosome 21. The percentage of cells wi th trisomy 21 in the probands' blood lymphocytes was 6%-34%. There wer e two classes of autoradiographic results: In class I, a ''third allel e'' 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 nondisjun ction (NDA) (trisomy 21 zygote) and subsequently lost one because of m itotic (somatic) error, the lost chromosome 21 being that with the low est-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 e ither by a postzygotic, mitotic error in a normal zygote that followed a normal meiosis (class IIA mechanism); by premeiotic, mitotic NDJ yi elding 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 fertilizat ion (class IIC mechanism). Among class II mechanisms, the most likely is mechanism IIA, while IIC is the least likely. There were 10 cases o f class I and 7 cases of class II results. Within class I, there were nine cases with maternal meiotic errors (six meiosis I and three meios is II errors, on the basis of pericentromeric markers) and one with pa ternal meiosis I error. The postzygotic loss of chromosome 21 was dete rmined in eight maternal class I cases, and it was maternally derived in five cases and paternally derived in three; this suggests that the postzygotic loss of chromosome 21 is probably random. The mean materna l age in meiotic class I errors was 31.4 years and in mitotic class II errors was 27.4 years, as expected.