Nondisjunction

Description

Chromosomal mosaicism as described here refers to a tendency to chromosomal nondisjunction. See also premature chromatid separation (PCS; 176430), which may also predispose to chromosomal nondisjunction.

Clinical Features

Hecht et al. (1964) reviewed evidence on the nonrandomness of chromosomal abnormalities, including Down syndrome (190685) and trisomy 18.

Hirschhorn (1968) and Weiner (1965) reported familial mosaicism. A 65-year-old man with classic chronic myeloid leukemia (CML; 608232) had the Philadelphia chromosome in all bone marrow and peripheral blood cells. His father died of leukemia of undetermined type and a brother and sister died of well-documented CML without chromosome studies. Three healthy offspring of the proband demonstrated mosaicism for the Philadelphia chromosome in peripheral blood cells.

Grell (1971) referred to 'distributive pairing' as a phenomenon occurring in man to explain aneuploidy. Baker et al. (1976) reviewed the evidence for meiotic mutants in man against the large body of information on such mutants in other species.

Inheritance

The occurrence of multiple cases of various aneuploid states in the same sibship or kindred has been interpreted by some as indicating a familial, presumably genetic, tendency to anaphase loss or nondisjunction (e.g., Boczkowski et al., 1969).

Zellweger and Abbo (1965) described mosaicism in 3 successive generations of a family. Clones with normal karyotype, D-G and D-D translocations, partial trisomy 21, and monosomy X were found. Because of an unusual frequency of satellite association, they postulated the existence of a 'dominant gene' that leads to mosaicism of somatic origin. The family was described in full by Abbo et al. (1966), who concluded that inheritance of a postulated gene for increased satellite association from both parents might lead to mosaicism.

De Bault and Halmi (1975) described mosaicism for trisomy 7 in a psychiatric patient and her daughter, who also had mental illness. The authors proposed autosomal dominant inheritance of a predisposing gene.

The possibility of autosomal recessive genes predisposing to nondisjunction was examined by Kwiterovich et al. (1966), who determined the frequency of Down syndrome in an inbred Amish population, and by Matsunaga (1966), who investigated the frequency of consanguinity in the parents of cases of Down syndrome. These studies gave no suggestion of inbreeding effect in contrast to the work of Gowen (1933) indicating such an effect in Drosophila and suggestive earlier work with Down syndrome.

Hirschhorn and Hsu (1969) and Hsu et al. (1970) described a family of Portuguese extraction, with second-cousin parents, in which 2 daughters had 45,X-46,XY-47,XYY mosaicism and a son had 46,XY-47,XYY mosaicism. A third daughter showed 5% aberrant cells (extra B group chromosome, extra small acrocentric chromosome, missing C group chromosome). The authors postulated an autosomal recessive gene which predisposes the homozygote to 'mitotic instability.' Others have proposed a dominant factor for nondisjunction.

In Kuwait, Alfi et al. (1980) found that Down syndrome was about 4 times more frequent among the children of closely related parents than among those with unrelated parents (p less than 0.005). By contrast, Devoto et al. (1985) could find no increased consanguinity in the parents or grandparents of Down syndrome cases.

Juberg et al. (1990) reported X-chromosome mosaicism in females of 3 generations. The phenotypic effect, if any, appeared to be limited to reduced fertility.

Warburton et al. (2004) commented that there are few data concerning the recurrence risk for individual trisomies or the risk for recurrence of trisomy for a different chromosome, despite the large number of prenatal diagnoses performed for the detection of trisomy. Recurrence of trisomy in the offspring of a couple could occur for several reasons: (1) chance alone, due to the maternal age-associated risk, (2) parental gonadal mosaicism for trisomy, or (3) factors associated with an increased risk of meiotic error. By analyzing records from prenatal diagnoses from 2 sources and using the standardized morbidity ratio (SMR), Warburton et al. (2004) compared the observed number of trisomies with the expected numbers, giving maternal age-specific rates. 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 (p = 0.0005). For heterotrisomy, the SMR after an index trisomy 21 was 2.3; the SMR did not vary with maternal age at the first trisomy. For prenatal diagnoses following a nonviable trisomy diagnosed in a spontaneous abortion, the SMR for a viable trisomy was 1.8. The significantly increased risk for heterotrisomy supported the hypothesis that some women have a risk for nondisjunction higher than do others of the same age.

Animal Model

Beadle (1932) described in maize a recessive gene, termed 'sticky,' which predisposed to mitotic nondisjunction. Lewis and Gencarella (1952) described a similar recessive mutation in Drosophila.

In mice, Hansmann and Jenderny (1983) found a suggestion of strain differences in frequency of aneuploidy.