Premature Chromatid Separation Trait

A number sign (#) is used with this entry because the premature chromatid separation (PCS) trait is caused by heterozygous mutation in the mitotic checkpoint gene BUB1B (602860) on chromosome 15q15.

See also mosaic variegated aneuploidy (MVA; 257300), which is a severe autosomal recessive developmental disorder caused by biallelic mutations in the BUB1B gene. MVA occurs when the offspring of 2 parents heterozygous for the PCS trait inherits both mutant BUB1B alleles.

Description

Premature chromatid separation consists of separate and splayed chromatids with discernible centromeres and involves all or most chromosomes of a metaphase. It is found in up to 2% of metaphases in cultured lymphocytes from approximately 40% of normal individuals. When PCS is present in 5% or more of cells, it is known as the 'heterozygous PCS trait' and has no obvious phenotypic effect, although some have reported decreased fertility (Gabarron et al., 1986). Inheritance is autosomal codominant (Kajii and Ikeuchi, 2004).

See also 158250 for a possible inherited predisposition to nondisjunction, which may be a related phenomenon.

Nomenclature

Kajii et al. (1998) referred to this condition as 'total premature chromatid separation' (total PCS) because the phenomenon involves not only the centromeres but also the entire chromatids.

As noted by Kajii and Ikeuchi (2004), 'premature chromatid separation (PCS)' is sometimes incorrectly referred to as 'premature centromere division (PCD).' PCD is a distinct entity; see 212790. Several references listed in this entry (e.g., Rudd et al., 1983; Gabarron et al., 1986) have incorrectly used the designation PCD when referring to PCS. To avoid confusion, we have changed the designation to PCS in our discussion of these references.

Clinical Features

Rudd et al. (1983) observed an increased frequency of mitoses with separated centromeres and splayed chromatids in the presence of colcemid in short-term lymphocyte cultures from 3 unrelated persons. The individuals were referred for chromosome studies: a 27-year-old woman with recurrent early spontaneous abortion; a 24-year-old male who had cancer radiotherapy for seminoma of the testes; and a 28-year-old woman with infertility. Whereas control cell cultures showed 0.5% to 1% mitosed demonstrating premature separation, cells from the probands and their affected family members showed 5% to 61.5% premature separation. In 2 of the 3 patients, the frequency of premature separation was reduced when colcemid was omitted but was still higher than in controls. Cultured fibroblasts from the third patient, whose cells showed no reduction with colcemid, exhibited increased tetraploidy and multinucleated cells. Cinematography of cell cultures showed a shortened metaphase time. Similar studies performed on multiple family members of each proband showed that transmission in each of the families was consistent with autosomal dominant inheritance; male-to-male transmission was shown in 3 instances in 2 families. Rudd et al. (1983) noted that the phenomenon was similar to that of PCD (212790), which is often found in phenotypically normal women.

Mehes (1978) investigated early centromere separation in 12 normal children, 14 patients with Down syndrome (190685), and 12 parents of children with autosomal trisomies. Mehes (1978) suggested that nonrandom centromere division may be a mechanism of nondisjunction.

Fitzgerald et al. (1986) reported a clinically normal 28-year-old woman who had 3 conceptuses with trisomy 21 and 1 normal child. Laboratory studies showed minimal evidence of mosaicism: 4% of blood cells and 6% of skin fibroblasts had trisomy 21. Also, 7% of her blood cells showed aneuploidy of the X chromosome which was associated with premature centromere separation of the X; 6% of fibroblasts showed trisomy 18; 10% of fibroblasts showed premature centromere separation of chromosome 21; 1% of fibroblasts showed PCS of chromosome 18. Since it was unlikely that this woman was a constitutional mosaic for trisomies X, 18, and 21, all at low levels, the authors suggested she was liable to PCS especially of those chromosomes.

Gabarron et al. (1986) reported a Spanish woman referred for chromosome analysis following 5 spontaneous abortions, 4 of which occurred in the first trimester. Other than short stature, the phenotype was unremarkable. Laboratory studies found premature chromatid separation in lymphocyte cultures from the proband, her mother, and a son and daughter, consistent with autosomal dominant inheritance. PCS was observed both in the presence and in the absence of colchicine. Cultured fibroblasts from the proband, on the other hand, showed only normal diploid metaphases. PCS cells appeared to have a shorter cell cycle.

Madan et al. (1987) described a family with 4 phenotypically normal persons in 3 successive generations who had an increased frequency of cells with premature centromere division of all chromosomes. PCS was observed in approximately 4 to 12% of cells. The phenomenon was considered to be different from the PCD of the X chromosome, and from the centromere splitting in cells of patients with Roberts syndrome (268300).

Bajnoczky and Mehes (1988) described 'out-of phase' centromere separation of the relevant chromosome, either early separation or late separation, in parents of offspring with trisomy 18 and trisomy 21. The findings provided further evidence for the correlation between alteration of parental centromere separation and aneuploidy in the offspring.

While evaluating individual mitoses for centromere separation, Mehes and Kosztolanyi (1992) found unusually late separation of chromosome 18 in a few cells of one of the parents in each of 3 families with a neonate with trisomy 18. The authors suggested that possible germline mosaicism of delayed separation in the parent might account for trisomy in the offspring. Chromosome 18 is normally the first to separate; chromosomes 2, 4, 5, 12, 17, and X also divide very early, whereas chromosomes 1, 11, 16, Y, and acrocentrics are the last to separate.

In both members of an ostensibly healthy but childless couple, Bajnoczky and Gardo (1993) found an increased frequency of mitoses with centromere separation affecting all chromosomes in lymphocyte cultures. The 37-year-old wife had had 3 spontaneous abortions in the first trimester. The authors suggested that the abnormal behavior of centromeres may have predisposed to cell division errors with spontaneous abortion as a consequence. The abnormality was referred to as 'premature anaphase.'

Mehes (1993) observed late division of chromosome 12 in a father and daughter and early separation in a father and son. However, this phenomenon may be only biologic variation with chance correlation across generations.

Petkovic (2007) reported a 3-generation family with autosomal dominant inheritance of PCS. Cytogenetic studies on peripheral blood lymphocytes demonstrated PCS frequency of 8.5% to 13.5% in 4 affected members. The 42-year-old proband and her 23-year-old son developed carcinoma in situ of the uterine cervix and keratoacanthoma, respectively. Both tumors were successfully treated surgically without chemotherapy or radiation and without recurrence. Petkovic (2007) suggested a possible association between the tumors and the PCS trait. No molecular studies were performed.

Diagnosis

Prenatal Diagnosis

Kajii and Asamoto (2004) reported prenatal diagnosis of a heterozygous carrier of the premature chromatid separation trait. The parents of 2 infants born with the homozygous PCS trait, or MVA syndrome, underwent chromosomal analysis. The father and mother had 6.5% and 16% PCS in cultured lymphocytes, respectively, consistent with heterozygosity for the PCS trait. Amniocentesis at 16 weeks in a subsequent pregnancy showed 4.5% cells in PCS and a nonmosaic 46,XY karyotype, also consistent with a heterozygous carrier of the PCS trait. A male infant was born with no malformations and no brain abnormalities. Cultured cord blood lymphocytes showed 16% cells in PCS.

Molecular Genetics

In a patient with MVA syndrome who was compound heterozygous for mutations in the BUB1B gene, Hanks et al. (2004) found that one mutation was inherited from the father and the other from the mother; both parents had PCS (see 602860.0009).