Tetraploid Partial Hydatidiform Moles Molecular Genotyping and Determination of Parental Contributions Jennifer Bynum, Denise Batista, Rena Xian, Deyin Xing, James R. Eshleman, Brigitte M. Ronnett, and Gang Zheng From the Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland Accepted for publication September 11, 2019. Address correspondence to Gang Zheng, M.D., Ph.D., Di- vision of Molecular Genetics and Genomics, Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN 55905; or Bri- gitte M. Ronnett, M.D., Department of Pathology, Johns Hopkins Hospital, Baltimore, MD 21287. E-mail: zheng. [email protected] or bronnett@ jhmi.edu. DNA genotyping studies have established that most partial hydatidiform moles (PHMs) are diandric dispermic triploid conceptions. Rare triandric tetraploid PHMs have been described, but genotyping cannot determine the manner in which three paternal chromosome complements are derived (one sperm with triplication, two sperm with one duplication, three different sperm, or one diploid and one haploid sperm). In a large prospective analysis of potentially molar products of conception, five tetraploid PHMs were encountered among 235 PHMs. Single-nucleotide polymorphism (SNP) arrays were used to define different paternal chromosomal contributions. Short tandem repeat analysis of the five tetraploid PHMs established that these contained three paternal and one maternal chromosome complements. In each case, the corresponding SNP array found five tracts with segmented absence of the central tract across approximately 25% of the genome. Meiotic crossovers could be observed directly in the chromosomes via the total number of starts and stops of regions of loss of heterozygosity. The findings are consistent with each conceptus having three different paternal contributions and one maternal contribution. These findings suggest that tetraploid PHMs arise when three different sperm fertilize a single, normal ovum. SNP array is useful to determine the parental contributions in triploid/tetraploid conceptuses. It also allows for direct visualization of meiotic crossover frequency and sites in these conceptions, providing insight into their biology. (J Mol Diagn 2020, 22: 90e100; https://doi.org/10.1016/ j.jmoldx.2019.09.006) Hydatidiform moles are abnormal placentas in which an excess of paternal relative to maternal DNA material is present. There are two types of hydatidiform moles: com- plete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs). CHMs are purely androgenetic conceptions (only paternal genetic material is present) and usually diploid (two paternal chromosome complements without a maternal chromosome complement). 1 Most result from fertilization of an ovum devoid of maternal genetic material by a single sperm that duplicates (monospermy; approxi- mately 85%; P 1 P 1 ), 2e4 but a subset is due to fertilization by two sperm (dispermy; P 1 P 2 ). 5 Some CHMs are tetraploid rather than diploid, but these are also purely androgenetic. In contrast, PHMs are characterized by diandric triploidy (two paternal and one maternal chromosome complements), with most arising by fertilization of an ovum by two sperm (dispermy; approximately 99%; P 1 P 2 M), with only rare examples that arise by fertilization of an ovum by one sperm that duplicates (monospermy; 1%; P 1 P 1 M). 2,4,6e10 These mechanisms of fertilization are illustrated in Figure 1. Rare examples of PHMs exhibit triandric tetraploidy (three paternal and one maternal chromosome comple- ments). 11 DNA genotyping by short tandem repeat (STR) analysis can determine that these rare triandric tetraploid PHMs are at least dispermic but cannot determine the Funding: None. B.M.R. and G.Z. contributed equally to this work. Disclosures: None declared. Current address of G.Z., Division of Molecular Genetics and Genomics, Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN. Copyright ª 2020 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jmoldx.2019.09.006 jmd.amjpathol.org The Journal of Molecular Diagnostics, Vol. 22, No. 1, January 2020
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