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Indian Pediatr 2009;46: 359-360

Double Aneuploidy with Down Syndrome

FJ Sheth and AG Shodhan

FRIGE, Institute of Human Genetics, Jodhpur Road, Satellite, Ahmedabad 380 015, Gujarat, India.
E-mail: [email protected]

Robertsonian translocations (RT) are one of the most common structural reorganizations with an incidence of 1/1000 newborns(1). The most prevalent heterologous RT is der(13;14) which makes up ~75% of all RT with an incidence of 0.97/1000 in newborn carriers, reaching frequencies up to nine times higher in infertile males(2).

The risk of unbalanced karyotype resulting from RT in spermatozoa lies between 3-27% depending on the specific chromosome involved in the translocation(3). The der(13;14) increases the risk of trisomy 13 to <2.7% in the 2nd trimester to <0.6% at live birth, trisomy 14 to 0.4% and raise the risk of spontaneous abortions to 20-22%(4). It has also shown an increased risk of trisomy of other chromosomes not involved in the translocation due to "interchromosomal effects"(1).

A young couple of non-consanguineous marriage approached for prenatal evaluation during their 4th pregnancy. Previously, they had two first trimester abortions and a child portraying clinical features of Down syndrome like flat nasal bridge, short neck, narrow palate, bilateral simian crease, epicanthic folds, small ears and open mouth. Chromosomal analysis of amniotic fluid fibroblast study revealed RT involving chromosome 13 and 14. To rule out de-novo origin of the translocation, the parents and the first child were karyotyped. It was found that the father is a balanced translocation carrier, 45,XY,der(13;14)(q10;q10) and the fetus had inherited RT from its father. The sibling was found to have double aneuploidy with karyotype, 46,XY,der(13;14)(q10;q10)pat,+21. The maternal karyotype is normal.

In this case, all the chromosome 21 present in the proband showed unusually long and typical satellite and hence, chromosome 21 satellites was used as a marker and the pattern compared with the parental chromosome 21, which confirmed the additional chromosome 21 to be of paternal origin. This could be due to "interchromosomal effect". The chromo-some 21 consistently showed a higher disomy frequency (0.22-0.55%) than other autosomes tested in translocation carriers(5). This signified that a translocation of chromosomes may lead to abnormal segregation of a chromosome not involved in the translocation during meiosis.

Hence, it is recommended to do a full karyotype in addition to FISH and it is also necessary to do karyotype in the previously affected child, before doing prenatal diagnosis. Thus, a couple in which one of the partners is a carrier of a balance translocation, genetic counseling is needed to discuss the fertility problems and the increased risk of a trisomy/monosomy of the translocated chromosome. One also needs to counsel them about the increased 1% additional risk of conceiving a trisomic child other than the chromosomes involved in the translocation.

References

1. Blouin JL, Binkert F, Antonarakis SE. Biparental inheritance of chromosome 21 polymorphic markers indicates that some Robertsonian translocations, t(21;21) occur post-zygotically. Am J Med Gene 1994; 49: 363-368.

2. Anton E, Blanco J, Egozcue J, Vidal F. Sperm FISH studies in seven male carriers of Robertsonian translocation t(13;14)(q10;q10). Hum Reprod 2004; 19: 1345-1351.

3. Shi Q, Martin RH. Aneuploidy in human spermatozoa: FISH analysis in men with constitutional chromosomal abnormalities, and in infertile men. Reproduction 2001; 121: 655-666.

4. Engel H, Eggermann T, Caliebe A, Jelska A, Schubert R, Schuler HM, et al. Genetic counseling in Robertsonian translocation der(13;14): frequencies of reproductive outcomes and infertility in 101 pedigrees. Am J Med Genet 2008; 146: 2611-2616.

5. Pellestor F, Imbert I, Andreo B, Lefort GS. Study of the occurrence of interchromosomal effect in spermatozoa of chromosomal rearrangement carriers by fluorescence in-situ hybridization and primed in-situ labeling techniques. Hum Reprod 2001; 16: 1155-1164.