Original Article Cytogenet Genome Res 2014;144:264–274 DOI: 10.1159/000381073
Accepted: February 2, 2015 by M. Schmid Published online: March 28, 2015
The Contribution of Germinal Mosaicism to Human Aneuploidy Harita Ghevaria a Sioban SenGupta a Urvashi Sarna b Susannah Sargeant b Paul Serhal b Joy Delhanty a a Preimplantation Genetics Group, Institute for Women’s Health, University College London, and b The Centre for Reproductive and Genetic Health, London, UK
Abstract Germinal mosaicism in a parent is considered to be a rare cause of aneuploidy in the offspring. The aim of this study was to assess the incidence of pre-meiotic errors, indicative of germinal mosaicism, leading to aneuploidy compared with those that occur at meiosis I. The material consisted of 126 oocytes, unexposed to sperm, donated by 57 women with an average maternal age of 35. The oocytes were at various stages of maturity and were analysed by array comparative genomic hybridisation. Of these, 102 gave conclusive results, comprising 47 that were immature, at the germinal vesicle (GV) or metaphase I stage (MI); 34 complete metaphase II-first polar body (MII-PB) complexes together with 21 incomplete complexes. Oocytes at the GV or MI stage provide direct evidence of pre-meiotic aneuploidy. Complete MII-PB complexes with the expected reciprocal gains/losses provide information on MI errors; those with non-reciprocal gains have pre-meiotic errors. Overall, 29 oocytes were aneuploid, and the source of the error was known for 21. In 8 (from 7 women) the error was pre-meiotic consisting of 4 MI oocytes and 4 MII-PB complexes with non-reciprocal gains.
© 2015 S. Karger AG, Basel 1424–8581/15/1444–0264$39.50/0 E-Mail [email protected] www.karger.com/cgr
The remaining 13 were the result of errors at meiosis I. Although pre-meiotic errors occurred in only 10% of informative oocytes, most notable was the fact that for those oocytes where the source of the error was known, 38% were caused by germinal mosaicism compared with 62% that were the outcome of a meiosis I error. None of the women with germinal mosaicism were infertile. © 2015 S. Karger AG, Basel
Human oogenesis begins before birth in the fetus. By the end of the third month in fetal development, the primordial germ cells have undergone multiple rounds of mitosis to form oogonia, which undergo pre-meiotic DNA replication, and the oocytes then enter the prophase of meiosis I. The oocytes continue through the leptotene, zygotene and pachytene stages of meiotic prophase I. Near the time of birth, all the oocytes have sequentially started the prophase of meiosis I and are arrested at the diplotene stage. These primary oocytes remain arrested in prophase and are characterised by a nucleus called the germinal vesicle (GV). This stage lasts for many years, and the oocytes do not finish their first meiotic division until after puberty. At puberty with each monthly cycle, the oocytes sequentially resume meiosis and proceed Harita Ghevaria Preimplantation Genetics Group, Institute for Women’s Health University College London 86–96 Chenies Mews, London WC1E 6HX (UK) E-Mail h.ghevaria @ ucl.ac.uk
Downloaded by: University of Cambridge 131.111.185.67 - 5/18/2015 12:26:24 PM
Key Words aCGH · Aneuploidy · Germinal mosaicism · Oocytes
through the metaphase I (MI) and anaphase I stages, and the mature gamete is formed after the completion of meiosis I with 23 chromosomes in the metaphase II (MII) oocyte and another 23 chromosomes in the first polar body (PB). Fertilisation occurs at this stage. However, human reproduction is an inefficient process. In fertile couples, the estimated chance of a clinically recognised natural pregnancy ranges from 22 to a maximum of 40% with timed insemination in young women (age
Accepted: February 2, 2015 by M. Schmid Published online: March 28, 2015
The Contribution of Germinal Mosaicism to Human Aneuploidy Harita Ghevaria a Sioban SenGupta a Urvashi Sarna b Susannah Sargeant b Paul Serhal b Joy Delhanty a a Preimplantation Genetics Group, Institute for Women’s Health, University College London, and b The Centre for Reproductive and Genetic Health, London, UK
Abstract Germinal mosaicism in a parent is considered to be a rare cause of aneuploidy in the offspring. The aim of this study was to assess the incidence of pre-meiotic errors, indicative of germinal mosaicism, leading to aneuploidy compared with those that occur at meiosis I. The material consisted of 126 oocytes, unexposed to sperm, donated by 57 women with an average maternal age of 35. The oocytes were at various stages of maturity and were analysed by array comparative genomic hybridisation. Of these, 102 gave conclusive results, comprising 47 that were immature, at the germinal vesicle (GV) or metaphase I stage (MI); 34 complete metaphase II-first polar body (MII-PB) complexes together with 21 incomplete complexes. Oocytes at the GV or MI stage provide direct evidence of pre-meiotic aneuploidy. Complete MII-PB complexes with the expected reciprocal gains/losses provide information on MI errors; those with non-reciprocal gains have pre-meiotic errors. Overall, 29 oocytes were aneuploid, and the source of the error was known for 21. In 8 (from 7 women) the error was pre-meiotic consisting of 4 MI oocytes and 4 MII-PB complexes with non-reciprocal gains.
© 2015 S. Karger AG, Basel 1424–8581/15/1444–0264$39.50/0 E-Mail [email protected] www.karger.com/cgr
The remaining 13 were the result of errors at meiosis I. Although pre-meiotic errors occurred in only 10% of informative oocytes, most notable was the fact that for those oocytes where the source of the error was known, 38% were caused by germinal mosaicism compared with 62% that were the outcome of a meiosis I error. None of the women with germinal mosaicism were infertile. © 2015 S. Karger AG, Basel
Human oogenesis begins before birth in the fetus. By the end of the third month in fetal development, the primordial germ cells have undergone multiple rounds of mitosis to form oogonia, which undergo pre-meiotic DNA replication, and the oocytes then enter the prophase of meiosis I. The oocytes continue through the leptotene, zygotene and pachytene stages of meiotic prophase I. Near the time of birth, all the oocytes have sequentially started the prophase of meiosis I and are arrested at the diplotene stage. These primary oocytes remain arrested in prophase and are characterised by a nucleus called the germinal vesicle (GV). This stage lasts for many years, and the oocytes do not finish their first meiotic division until after puberty. At puberty with each monthly cycle, the oocytes sequentially resume meiosis and proceed Harita Ghevaria Preimplantation Genetics Group, Institute for Women’s Health University College London 86–96 Chenies Mews, London WC1E 6HX (UK) E-Mail h.ghevaria @ ucl.ac.uk
Downloaded by: University of Cambridge 131.111.185.67 - 5/18/2015 12:26:24 PM
Key Words aCGH · Aneuploidy · Germinal mosaicism · Oocytes
through the metaphase I (MI) and anaphase I stages, and the mature gamete is formed after the completion of meiosis I with 23 chromosomes in the metaphase II (MII) oocyte and another 23 chromosomes in the first polar body (PB). Fertilisation occurs at this stage. However, human reproduction is an inefficient process. In fertile couples, the estimated chance of a clinically recognised natural pregnancy ranges from 22 to a maximum of 40% with timed insemination in young women (age
