Purpose: To evaluate the sensitivity, specificity, advantages, and limitations of multiplex ligation-dependent probe amplification compared with conventional karyotype analysis in the investigation of contributing factors to recurrent pregnancy loss. Method: A cohort of 284 patients underwent side-by-side analysis of products of conception by both conventional karyotyping and multiplex ligation-dependent probe amplification with direct comparison of results. Results: Multiplex ligation-dependent probe amplification was shown to enable a diagnosis for an additional 47 (16.5%) patients compared with conventional karyotype analysis. However, this advantage was offset by some disadvantages of the method, including a high false-positive rate (8/104; 7.7%), as demonstrated by single-arm probe abnormalities of uncertain clinical significance, as well as the inability to characterize structural rearrangements, such as Robertsonian translocations, which comprised 2.46% of samples (99% confidence interval ϭ 0.09 -4.83), and ploidy changes. The calculated performance characteristics of multiplex ligation-dependent probe amplification in this cohort yielded a sensitivity of 86.9% and specificity of 92.4%. Conclusions: The advantages of now widely accepted molecular methodologies, such as lower failure rates, faster turnaround times, and lower cost, must be complemented by adequate counseling, family follow-up, and specific diagnostic reporting practices. It is particularly important to specifically address the important limitations of the methodology, including the inability to characterize balanced structural rearrangements and ploidy changes, especially if multiplex ligation-dependent probe amplification is to be performed alone. Genet Med 2011:13(1):46 -51. Key Words: recurrent pregnancy loss, products of conception, genetic diagnosis, cytogenetics, multiplex ligation-dependant probe amplificationA proximately 15-20% of recognized pregnancies end in a spontaneous abortion before 20 weeks gestation. The burden of pregnancy loss is, however, not uniformly distributed. As a result of the increase in the risk of trisomic pregnancies with advancing maternal age, Ͼ40% of pregnancies in women older than 40 years end in spontaneous abortion. Recurrent pregnancy loss (RPL) is also frequent, affecting approximately 5% of couples. The major factors contributing to pregnancy loss are chromosomal in origin with approximately 50% of products of conception (POC) demonstrating either aneuploid or polyploid karyotypes. 1,2

In 3,000 women referred for prenatal diagnosis, 110(3.7%) abnormal fetuses were detected and 85 therapeutic terminations were performed. These were five main reasons for referral. Among the 2,227 women referred because of maternal age 35 years and older, there were 51 (2.3%) who had aneuploid fetuses. In the 297 women referred because of a previous child with Down syndrome, 3 aneuploid fetuses (1.0%) were detected. Of the 55 couples where one spouse was a carrier of a balanced chromosome rearrangement, 6 chromosomally abnormal fetuses were found (10.9%) (all the offspring of maternal carriers). In the latter group, five of the six heterozygotes with abnormal findings were carriers of tdic (13;21) translocations. In the 82 cases with a history of X-linked disorders, there were 40 males (49%). Thirty-five women were referred because of inborn errors of metabolism: 10 affected fetuses were found (28%). There was a greater proportion of sex-chromosome aneuploids as compared to trisomy 21 fetuses in the 35 to 39 year maternal age group. This was reversed in the group of women 40 years old and older. Of the 25 abnormal fetuses not terminated, 6 were sex chromosome aneuploids and 10 involved X-linked conditions where the progeny could be further prenatally monitored (eg, X-linked hydrocephalus) or treated (eg, hemophilia). In the remaining 9 the parents expressed divers reasons for their choice. Repeat amniocentesis was required in 2.9% of cases. One case of maternal cell contamination and one case of unconfirmed mosaicism were the only diagnostic errors found in the study. In the last 1,000 specimens referred, the average time necessary for a karyotypic result was 15.6 +/- 5.6 days after amniocentesis.

SUMMARY A new dicentric X isochromosome i(X)(pter-*q2102-*pter) of similar size to a normal X is described in a girl with gonadal dysgenesis. In this non-mosaic case with an X short arm duplication, most of the stigmata associated with Turner's syndrome were absent. This structure was compared with that of six i(Xq) and three del(X (1977), Niebuhr and Skovby (1977), and Verlinskaya and Mashkova (1977). Of considerable interest and significance as to their genesis is the proportion of isochromosomes that prove to be dicentric. Centromeric misdivision was proposed as the mechanism of origin of isochromosomes by Darlington (1939), who also predicted the existence of dicentric isochromosomes which he termed isodicentrics (Darlington and Wylie, 1953). This concept was developed in human material (de la Chapelle et al., 1966) and possible infracentromeric breakpoints and dicentric-producing long or short arm breaks were described. Therman et al. (1974) showed that dicentric X structures such as end-toend X fusions fitted the model of Gl chromatid break with G2 sister chromatid reunion, producing a dicentric chromatid at the following anaphase. A second alternative proposed by Therman et al. was a G2 chromatid exchange after homologous pairing of the adjacent type, analogous to the U type exchanges within a bivalent observed in plants (Jones, 1969). Though the existence of Xp isochromosomes has been doubted after the reinterpretation of one as an Xq deletion (de la , it has been suggested (Howell

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