Chromosome Abnormalities and Genetic Counseling , 3rd Edition

7.Centromere Fissions, Complementary Isochromosomes, and Telomeric Fusions

This chapter provides a setting for certain very rare abnormalities that cannot easily be accommodated elsewhere. Centromere fission results when a metacentric or submetacentric chromosome splits at the centromere, giving rise to two stable telocentric products. In a sense, this is the reverse of what happens in the Robertsonian fusion. The heterozygote, a phenotypically normal individual, thus has 47 chromosomes. Only eight such families have been published. Similarly rare, with just six reported cases, is the balanced complementary isochromosome carrier. Here, two stable exactly metacentric products are generated. Telomeric fusion (10 families known) leads to a 45 chromosome count, due to the joining up of two chromosomes, tip to tip, not unlike the Robertsonian mechanism. The fusion chromosome has two centromeres, but one of these becomes inactivated.

BIOLOGY

Centromere Fission

A nonacrocentric chromosome undergoes a horizontal splitting at the centromere (Fig. 7-1a) (Rivera and Cantú, 1986). Two new telocentric chromosomes result (Fig. 7-2). One comprises the short arm of the original, and the other its long arm. It is as though the cell ignores the fact that the split happened, and continues on normally, treating each part as a properly functioning whole. The other normal homolog remains intact. The heterozygous person (47,cen fis) may have a balanced complement of genetic material, and thus be phenotypically normal. Among the eight families on record (Del Porto et al., 1984; Elakis et al., 1993; Bogart et al., 1995), just five chromo-somes—4, 7, 9, 10, and 21—have been involved.

At meiosis in the heterozygote, the centric fission products presumably form a trivalent with the intact homolog, and 2:1 segregation, essentially as in the Robertsonian carrier, then follows. “Alternate” 2:1 segregation produces normal and balanced centric fission gametes, while adjacent 2:1 segregation leads to gametes disomic or nullisomic for either of the fission products (Fig. 7-3). Monosomy would probably be associated with occult abortion and trisomy with miscarriage or, in exceptional cases, with the live birth of an abnormal child. Thus far, trisomies for only 4p and 9p are on record.

The paucity of data does not allow for a precise assessment of the genetic risk run by the centric fission carrier, other than to suggest that it could in some be quite high. Dallapiccola et al. (1976) reported a chromosome 4 centric fission in a woman who had had two children with trisomy 4p and one normal child. Fryns et al. (1980) describe a man and his normal daughter having a centric fission of chromosome 10. Elakis et al. (1993) record centric fission of chromosome 10 in a normal woman and her phenotypically abnormal fetus; the fetal defect was presumed to be coincidental. Recurrent abortion in the family of Janke (1982) may well have been a result of asymmetric segregation of a chromosome 7 centric fission. Bogart et al. (1995) record a de novo cen fis(21) in a normal child, identified at routine amniocentesis. Whether this might imply a genetic risk in the next generation, with the possibility of asymmetric segregation of the 21q elements and a child with Down syndrome, is at this point speculative.

Figure 7-1. Comparison of the processes of (a) centric fission and (b) complementary isochromosomes. The chromosome pairs at the outset (left), presumed to be existing in the zygote, have replicated to give the double-chromatid state. The jagged arrow indicates misdivision of the centromere in one homolog. By the time the cell enters the first mitotic division (right), the abnormal states have been generated. Note that, according to the proposed mechanism in (b), uniparental isodisomy would necessarily result. Open, original homolog from one parent; crosshatched, original homolog from the other.

Figure 7-2. Partial karyotype from a case of 47,fis(7). One no. 7 exists as a normal homolog, and the other homolog is represented by the 7p and the 7q chromosomes.

Extremely Rare Complexities

A centric fission may lead to the formation of an isochromosome for one arm of the chromosome, while the other whole arm translocates to the telomere of another chromosome; in this circumstance, the resulting imbalance is a pure trisomy for the arm that comprises the isochromosome. Sidwell et al. (2000)report such as case: an abnormal adolescent having, along with one normal chromosome 20, an i(20p)—thus, trisomy 20p—along with a nonreciprocal product consisting of a whole 20 long arm fused to a no. 4, at 4pter.

A unique case in Fryns et al. (1985) offers a variation on the theme of centromere fission. A mother had deleted an interstitial segment of one of her no. 7 chromosomes, from the centromere to band q21 in the long arm, and this 7(cen-q21) segment existed as a free supernumerary chromosome. The remaining part of 7q, from q21 to qter, joined back on to the original centromere. Since the supernumerary chromosome was mitotically stable, it presumably included functional centromeric material. Her karyotype was balanced. She had had two severely malformed infants who inherited the deleted chromosome, 46,del(7)(cen-q21), but not the supernumerary 7q chromosome, in whom, therefore, the constitutional state was a monosomy for the interstitial segment.

Figure 7-3. The six possible gametes arising from 2:1 segregation in a 47,cen fis(9) heterozygote. Two of these would be normal, the 46,N and the balanced 47,cen fis(9) states. Of the unbalanced states, only the 47,fis(9),+9p, in which the imbalance would be a 9p trisomy, might possibly be viable.

Complementary Isochromosomes

A not dissimilar case is the balanced isochromosome carrier: the complementary short arm and long arm (p, q) isochromosome heterozygote. Chromosomes 1, 2, 4, 7, and 9 have been reported with this picture. The individual has a full complement of the chromosomal material, but with the two p arms combined in one chromosome and the two q arms in the other (Fig. 7-4). The usual mechanism may be that, in the zygote, horizontal fission at the centromere of one homologous chromosome produces not two telocentric products (as happened in the fission, above) but two mirror-im-age metacentric chromosomes: an i(p) and an i(q) chromosome (Fig. 7-1b). This is followed by segregation of both isochromosomes into one daughter cell. There is loss (if it had ever been there) of the homologous normal chromosome contributed by the other parent (unlike the centric fission, in which the normal homolog is necessarily retained). The generation of the isochromsomes has the end result of a uniparental isodisomy, which in most reported patients has been a maternal UPD. In two cases, both with the karyotype 46,i(7p),i(7q), the 7p isochromosome was of paternal origin, and the 7q isochromosome was maternally derived (Kotzot et al., 2001a). An unbalanced circumstance exists if a normal homolog is retained, as van den Berg et al. (1999) document in a fetus with nonmosaic 47,+18,+i (18p),+i(18q).

Figure 7-4. Chromosomes from a woman with complementary isochromosomes i(2p) and i(2q) (see Fig. 7-1b). (Case of A. A. Schinzel; Bernasconi et al., 1996).

The usual clinical presentation has been multiple miscarriage in phenotypically normal women (Albrecht et al., 2001). Some with phenotypic abnormality may reflect the effects of a concomitant placental mosaicism, or of “unmasking” of a recessive gene due to uniparental isodisomy, such as the i(1p),i(1q) described in Chen et al. (1999c). A formal karyotype might be written, for example, as 46,XX,i(4)(p10), i(4)(q10). Rather analogous to the rob(21q21q) carrier (p. 136), it is practically impossible for such a person to have a normal child. Any pregnancies from “symmetric” segregation would be either dup(p)/del(q) or dup(q)/del(p), and thus hugely imbalanced.

Telomeric Fusion

This is the tip-to-tip fusion of two complete, or practically complete, chromosomes, and the person thus has a 45-chromosome count. The fusion occurs at the level of the telomere or the subtelomeric region. All the necessary functional genetic material is present and correct (if there is a missing bit, it contains no crucial genes), and the phenotype is normal, other things being equal. The composite chromosome has two centromeres (hence an alternative name of “stable non-Robertsonian dicentric chromosome”), but one of the two centromeres becomes functionally suppressed. The karyotype is written 45,t(A;B) or 45,dic(A;B), where A and B denote the two chromosomes. The short arm of an acrocentric chromosome is very frequently involved, and chromosome 18 is often one of the participating chromosomes. It is certainly rare, and, as a balanced constitutional karyotype, only just reaches double figures in literature reports (Engelen et al., 2000a; Lemyre et al., 2001). Ascertainment is typically fortuitous, or through reproductive difficulty (recurrent miscarriage, gonadal dysgenesis, oligoteratospermia). Familial transmission is recorded. The attachment of an essentially complete long arm of an acrocentric chromosome to the telomeric region of another autosome is a very similar circumstance (Fig. 7-5).

A normal child could be produced following symmetric, essentially 2:1 segregation: that is, either the two normal homologs are transmitted, or the composite chromosome. Asymmetric segregation, were it to happen, would lead to trisomy or monosomy of one of the component chromosomes, and, according to the nature of the chromosome, in utero viability would be compromised. For example, Lemyre et al. (2001) document a 45,XX,dic(14;18) (p11.2;p11.3) mother who was diagnosed at 32 weeks gestation with intrauterine fetal death. The fetal pathology examination was consistent with trisomy 18, and the karyotype, 46,XY, 18,dic(14;18)(p11.2;p11.3), confirmed this diagnosis. If the trisomic state were to be “corrected” by loss of the normal homolog from the other parent, a uniparental disomy would result. The case shown in Figure 7-5 is an example of this.

Figure 7-5. A telomeric fusion translocation, 45,XY, t(8;15)(p23.3;q11). The normal father with this karyotype has all the functionally necessary part of chromosome 15 attached to the telomere of a no. 8. His child with Angel-man syndrome has the same karyotype, but haplotyping with DNA markers showed that both chromosome 15 elements derived from the father, with no chromosome 15 contributed from the mother. Probably, this reflected a “corrected” interchange trisomy. (Case of A. Smith; Smith et al., 1994).

GENETIC COUNSELING

Centromere Fission

The centric fission heterozygote has a significant risk of having a phenotypically abnormal child in those cases in which a whole arm aneuploidy is viable. The 4p and 9p trisomies are the only examples known so far. It is most unlikely that any combination other than the short arm trisomy could be viable. A range of 5% to 25% is an educated guess of the likely risk. Prenatal testing is certainly advisable. Of the phenotypically normal offspring of the heterozygote, half would be expected to have the centric fission and half to have normal chromosomes. For the heterozygote in whom neither whole arm imbalance is viable—an obvious example would be a 47,fis(1)—no risk for a liveborn abnormal child exists.

Complementary Isochromosomes

In contrast, the carrier of the complementary p/q isochromosome carrier, essentially with certainty, cannot have a normal child.

Telomeric Fusion

Infertility may be frequent. If conception is possible, there is likely to be a substantial risk for aneuploidy of one or other of the chromosomes involved in the translocation but equally, a normal child could be conceived. Uniparental disomy must be considered, at least if chromosome 15 is involved.