Report of some cases with chromosomal mosaicism in prenatal diagnosis and the corresponding results after birth

Chromosomal mosaicism in prenatal diagnosis is a complex problem that confuses the perception of true mosaicism or pseudomosaicismand often causes difficulties in genetic counseling. In this study, the authors reported 5 cases of chromosomal mosaicism in prenatal karyotype diagnosisand compared them withthe corresponding karyotype results of children after birth. Amniotic fluid and peripheral blood cells were prepared chromosomal metaphase by culture method and chromosomal analysis according to ISCN 2016 standards. Samples were collected and analysed at Hanoi Medical University Hospital from 2017 to 2020. There were 3 cases of abnormal prenatal chromosomal mosaicism, but the postnatal results were normal, two cases of abnormal prenatal chromosome mosaicism, but had abnormal peripheral blood postnatal chromosome results. These results, together with discussion, will provide more valuable information for the prognosis of chromosome mosaicism cases in prenatal diagnosis and give better genetic counseling for the patients.

The true incidence of chromosomal mosaicism after preimplantation genetic testing is much lower than that indicated by trophectoderm biopsy

STUDY QUESTION What is the true incidence of chromosomal mosaicism in embryos analyzed by preimplantation genetic testing (PGT) SUMMARY ANSWER The true incidence of chromosomal mosaicism is much lower than we usually surmise. WHAT IS KNOWN ALREADY In recent years, contemporary methods for chromosome analysis, along with the biopsy of more than one cell, have given rise to an increased rate of chromosomal mosaicism detection after preimplantation genetic testing for aneuploidy. However, the exorbitant incidence of mosaicism represents a dilemma and imposes restrictions on the application of PGT treatment. Concern has been raised about the possibility that the incidence of chromosomal mosaicism is overestimated and quite a few of the results are false-positive errors. However, studies verifying the diagnosis of chromosomal mosaicism and assessing the true incidence of chromosomal mosaicism are limited. STUDY DESIGN, SIZE, DURATION A total of 1719 blastocysts from 380 patients who underwent PGT treatment were retrospectively analyzed to evaluate the typical incidence of mosaicism. Then 101 embryos donated by 70 couples were re-biopsied and dissected into three portions if available: trophectoderm (TE), inner cell mass (ICM), and the remaining portions. All the portions were tested using next-generation sequencing (NGS), and the results were compared to the original diagnosis. PARTICIPANTS/MATERIALS, SETTING, METHODS The setting for this study was a university-affiliated center with an in-house PGT laboratory. All samples were amplified with multiple annealing and looping-based amplification cycles (MALBACs) and the NGS was carried out on a Life Technologies Ion Proton platform. MAIN RESULTS AND THE ROLE OF CHANCE A clinical TE biopsy revealed an incidence of 11.9% for diploid-aneuploid mosaicism (DAM), 17.3% for aneuploid mosaicism (AM) and 29.1% in total. After rebiopsy, 94.1% whole-chromosome aneuploidies and 82.8% segmental-chromosome aneuploidies were confirmed in the embryos. As for the mosaic errors, only 32 (31.7%) out of 101 embryos presented with uniform chromosomal aberrations in agreement with the original biopsy results, 15 (14.8%) embryos presented with de novo chromosomal aberrations, and 54 (53.5%) embryos showed a euploid profile in all portions. Among the 32 uniform embryos, the true mosaicism was confirmed in only 4 cases, where a reciprocal chromosomal aberration was identified; 14 embryos presented with identical mosaicism, providing the moderate evidence for true mosaicism; and 14 embryos displayed uniform full aneuploidies in all portions of embryo, revealing a high-grade mosaicism or a false-negative diagnosis. Logistical regression analysis revealed that the concordance rate with ICM was associated with the type and level of mosaicism. The concordance rate of segmental-chromosome mosaicism was significantly lower than whole-chromosome mosaicism (adjusted Odds Ratio (aOR): 5.137 (1.061, 24.876), P = 0.042) and compared to DAM, the concordance rate of AM was significantly higher (aOR: 6.546 (1.354, 31.655), P = 0.019). The concordance rate also increased with increasing levels of mosaicism (P < 0.001). LIMITATIONS, REASONS FOR CAUTION This study was limited by a small sample size and the use of a single whole-genome amplification (WGA) method and NGS platform. These findings are only applicable to samples subjected to MALBAC amplification and Ion Proton platform, and studies involving larger sample sizes and multiple WGA methods and NGS platforms are required to prove our findings. WIDER IMPLICATIONS OF THE FINDINGS TE biopsy is reliable to detect whole-chromosome aneuploidies, but the ability to diagnose mosaicism is doubtful. More attention should be paid to false-positive and false-negative errors in NGS-based PGT, especially for laboratories using less stringent criteria for mosaicism classification (i.e. 20–80%), which might be subject to a much higher false-positive mosaicism rate in the practice. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the National Key R&D Program of China (No. 2016YFC1000206-5) and the National Natural Science Foundation of China (No. 81701509) TRIAL REGISTRATION NUMBER N/A.

Detectable chromosome X mosaicism in males is rarely tolerated in peripheral leukocytes

Age-related male Y and female X chromosome mosaicism is commonly observed in large population-based studies. To investigate the frequency of male X chromosome mosaicism, we scanned for deviations in chromosome X genotyping array intensity data in a population-based survey of 196,219 UK Biobank men. We detected 12 (0.006%) men with mosaic chromosome X gains ≥ 2 Mb and found no evidence for mosaic chromosome X loss, a level of detection substantially lower than for autosomes or other sex chromosomes. The rarity of chromosome X mosaicism in males relative to females reflects the importance of chromosome X gene dosage for leukocyte function.

Pregnancy outcomes in female patients with X chromosome mosaicism after the first IVF/ICSI treatment: A 6-year retrospective cohort study

Objective: The present study focused on the clinical pregnancy and cumulative live birth rate (CLBR) of female patients with X chromosome mosaicism (XM) after the first in-vitro-fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment, and the possible impact of different mosaic subtypes. Design: Retrospective cohort study Setting: Single Center study Population: Infertility couples Methods: In total, 76 couples with XM female partners and normal male partners were included (2014–2019) as the X group, with another 76 couples with normal karyotype included as the control group. Subgroup X1 included 41 45,X/46,XX cases, Subgroup X2 included 22 47,XXX/46,XX cases, and Subgroup X3 included 12 45,X/47,XXX/46,XX cases. Main Outcome Measures: The ovarian stimulation, embryo results and pregnancy outcomes were analyzed. Results: The X group presented similar CLBR but required a higher total gonadotropin (Gn) dosage than the control group (1800 IU vs. 1612 IU). Following subgroup analysis, the number of follicles during oocyte retrieval and average number of fertilized oocytes was lower in subgroup X1 than in X3. The clinical pregnancy rate and CLBR were similar in all groups. Conclusion: Females with XM may present a similar CLBR until one year after oocyte retrieval, but may require a higher total Gn dosage. Females with 45,X cells may recover fewer follicles during oocyte retrieval, resulting in fewer embryos. A higher 45,X cell ratio (over 5%) may lead to a lower CBLR. Funding: This study was supported by the Ministry of Science and Technology of China (2016YFC1000602). Keywords X chromosome mosaicism, IVF/ICSI outcome, cumulative live birth rate

XXY JOURNEY PROBLEMATIKA INDIVIDU INTERSEKS DALAM DRAWING DENGAN METODE AUTOETNOGRAFI

Keberadaan individu interseks berikut segala isu yang terkait dengan eksistensi mereka bukanlah hal yang baru dalam masyarakat, eksistensi interseks adalah sebuah kasus nyata dan bukan hanya dongeng tentang hermaprodit yang berasal dari mitologi Yunani. Pada abad 8 M, catatan keputusan hukum Islam membahas individu-individu yang dikenal dalam bahasa Arab sebagai khuntha dan PBB menyatakan sekitar 1,7% penduduk dunia adalah interseks. Dalam istilah Bahasa Indonesia, seringkali digunakan istilah kerancuan kelamin atau kelamin ganda. Interseks atau saat ini disebut DSD (Disorders of Sex Development). Latar belakang penulis yang terlahir interseks dengan kromosom 47XXY chromosome mosaicism penulis terdorong untuk berbagi pengalaman, mengalami sebagai individu interseks memaparkan kompleksitas dan problematika individu interseks dari masa anak-anak hingga dewasa, dengan pendekatan yaitu metode autoetnografi dalam penciptaan karya drawing dengan visual self portrait, penerapan metode Autoethografi juga dilakukan untuk memahami diri sendiri (self-narative) melalui penciptaan karya drawingKata kunci: Interseks, Autoetnografi, drawing.

The Karyotype Analysis of Sex Chromosome Mosaicism in Prenatal Diagnosis and Their Clinical Outcomes

Objective To analyze the karyotype of sex chromosome mosaicism in our prenatal diagnosis of 14034 pregnant women in their second trimester, and report the rate of sex chromosome mosaicism and their clinical outcomes.Methods A retrospective analysis of cytogenetic studies of 14043 cases of pregnant women from the Genetic Counseling Clinic from May 2017 to January 2020 by amniocentesis, were performed. Results A total of 46 cases of sex chromosome mosaicism were found, and the sex chromosome mosaicism rate was 0.328%, mainly including four types of mosaicism: mos45,X/46,XX(12); mos45,X/46,XY (11); mos47XXX(or XXY or XYY)/46XX(or XY)(11); and other types of complex abnormal karyotype mosaic(12). Among the 46 fetuses with sex chromosome mosaicism, the indications of prenatal diagnosis includes the numerical abnormality of sex chromosome by NIPT(23/46)，the high risk of trisomy 21 by serum screening(12/46)，abnomal ultrosound(4/46), the advanced maternal age(age ≥35)(4/46), and the histories of abnormal pregnancy(3/46). According to the results of cytogenetic analysis and genetic counseling, the pregnant women would decide to continue or terminate their pregnancy. Conclusion Prenatal cytogenetic diagnosis by amniocentesis is an accurate and convenient method and helps to avoid the delivery of fetuses with chromosomal diseases and reduce the risk of fetal malformation.

IVF and ICSI outcomes of female patients with X chromosome mosaicism: A 5-year retrospective cohort study

BackgroundThis study focused on the assisted reproductive treatment (ART) outcomes of female patients with X chromosome mosaicism (XM), who underwent their first IVF/ICSI and day 2 or day3 fresh embryo transfer, and the possible impacts of the different mosaic types.Results78 couples with XM female and normal male were included as the X group. 78 couples with normal karyotype were included as the control group. Subgroup X1 included 41 45,X/46,XX cases, Subgroup X2 included 23 47,XXX/46,XX cases, and Subgroup X3 included 13 45,X/47,XXX/46,XX cases. With similar female age and similar body mass index (BMI), the X group had higher total gonadotropin (Gn) dosage than the control group (1800 IU VS 1612 IU). In subgroup analysis, the follical number during oocyte retrieval was less in subgroup X1 than that in X2 or X3. The fertilization rate was lower in subgroup X1 than that in subgroup X2. The utilization rate was higher in subgroup X2 than that in subgroup X3. The implantation rate, clinical pregnancy rate, and miscarriage rate before 12 weeks' gestation were similar in all groups.ConclusionsFemale with 45,X cell line may face higher Gn dosage, less follical number during oocyte retrieval and fewer embryos. But female with X chromosome mosaicism may have similar clinical pregnancy rate and miscarriage rate after fresh embryo transfer.

SUN-091 Change in Sex of Rearing in Individuals with Disorders of Sex Development

Introduction: Differences of Sex Development (DSDs) encompass variations in formation of internal or external sex characteristics. Historically, sex assignment in children with DSDs depended on phenotype, and gender was thought to be malleable. Attention in DSD has recently shifted toward reducing gender dysphoria and preserving fertility potential. Our multidisciplinary DSD clinic was formed in 2008 with these goals and includes specialists from Endocrinology, Gynecology, Urology, Psychology, Social Work, Genetics, and Chaplaincy. Subjects: A chart review was done on all patients seen in our DSD clinic between April 2008 and June 2019 to determine rates of sex reassignment and gender dysphoria. Two hundred patients were seen: 23 were found to not have DSDs; 61 were 46,XX; 66 were 46,XY; 31 had a sex chromosome DSD; 5 had gonadal dysgenesis without known chromosome mosaicism; and 14 had syndromic genital atypia. Mean age of follow-up is 8.77 years. Results: Only 2 patients underwent sex reassignment at our institution. One was assigned male at birth, but was found to be 46,XX with 21-hydroxylase deficiency and was reassigned female at 1 month of age. The second was assigned male at birth and was found to be 46,XY with an NR5A1 variant. Sex was reassigned female at two months of age. Two additional patients had a sex reassignment outside our institution. One was born abroad and assigned male at birth. The patient was found to be 46,XY with an NR5A1 variant, and was reassigned female. The second patient was assigned male at birth, but was found to be 46,XX with P450 oxidoreductase deficiency. The parents changed the sex of rearing to female at 19 months of age. To date, none has signs of gender dysphoria. A total of three patients experienced gender dysphoria and underwent transition. The first had genital ambiguity with sex chromosome mosaicism in the gonads and was assigned female at birth. We held care conferences with the family and discussed the possibility of gender dysphoria. At age 3, the patient declared that he was male, and parents socially transitioned him at that time. Two were assigned female after receiving the diagnosis of 46,XX 21-hydroxylase deficiency. Both declared male gender identity later, one at 12.5 years of age, and one at 20.5 years of age. Conclusion: Whereas our patient population is still relatively young, it is reassuring that the overall rate of gender dysphoria is low. The rate in patients with CAH is similar to previous reports in the literature. Careful attention to sex assignment in early childhood may reduce the rates of gender dysphoria in children with DSDs.