Analysis of assisted pregnancy outcomes of ring chromosome carriers

doi:10.3877/cma.j.issn.1673-5250.2024.01.008

Objective

To investigate the clinical characteristics and pregnancy outcomes of ring chromosomes (RC) carriers. The embryonic aneuploidy rates and karyotype distribution were analyzed to evaluate the effect of RC on embryos.

Methods

A retrospective cohort study was conducted with 7 patients with RC seeking fertility treatment from March 2014 to April 2022 in the Reproductive Hospital Affiliated to Shandong University. The clinical features and pregnancy outcomes were recorded. For RC carriers underwent preimplantation genetic testing for aneuploidy (PGT-A), the aneuploidy rate and distribution of embryonic chromosomal aberrations were also analyzed. This study was approved by the Medical Ethics Committee of the Reproductive Hospital Affiliated to Shandong University (Approval No. [2021] 130), and informed consent was obtained from each patient.

Results

①The current study comprised 7 RC carriers (patient 1-7), including 2 female carriers (patient 1-2) and 5 male carriers ( patient 3-7). Patient 1 had an RC 7, manifesting decreased ovarian reserve. Patient 2 was diagnosed with premature ovarian insufficiency (POI), with a mosaic RC X. Interestingly, all the 5 male RC carries showed oligospermia or azoospermia, despite the karyotypes were different. ②Four RC carriers underwent PGT-A, including 1 female (patient 1) and 3 male carriers (patient 3, 5, 7). In total, 33 embryos were tested by PGT-A. After analysis, 24.2% (8/33) embryos were euploid, 63.6% (21/33) were aneuploid, 12.1% (4/33) were mosaic. Moreover, the frequency of embryos with ring chromosome related abnormalities was 32.0% (8/25). No difference of aneuploidy rate was observed between male and female RC carriers (P>0.05). Nonetheless, female RC carriers showed more embryos with ring chromosome related abnormalities than male carriers did (P<0.001). ③Four RC carriers (patient 2, 4, 6, 7) received oocyte/sperm donation.

Conclusions

RC carrier, especially female carriers, have a low rate of embryo euploidy. PGT is a preferred recommendation in order to reduce the risk of adverse pregnancy due to embryonic factors. All the male patients with an RC21 showed oligospermia or even azoospermia, indicating that the alteration or destruction of the spatial structure of chromosome 21 may affect the function of key genes involved in spermatogenesis, the underlining pathogenesis are warranted.

Key words: Ring chromosome, Preimplantation genetic testing, Genetic counseling, Clinical research

表1 本组7例环状染色体携带者的临床特征

患者编号	染色体核型^a	年龄(岁)		性别^a	身高^a(cm)	人体质量指数^a(kg/m²)	抗苗勒管激素^a(ng/mL)	窦卵泡计数^a(枚)	精子数^a(个/HP)	配偶染色体核型
患者编号	染色体核型^a	患者	配偶	性别^a	身高^a(cm)	人体质量指数^a(kg/m²)	抗苗勒管激素^a(ng/mL)	窦卵泡计数^a(枚)	精子数^a(个/HP)	配偶染色体核型
1	46，XX，r(7)(p22q36)	26	24	女	143	22.82	1.19	7	—	46，XY
2	mos45，X[52]/46，X，r(X)(p22q27)[48]	28	33	女	150	17.97	<0.06	0	—	46，XY
3	46，XY，r(21)(p11.1q22)	27	24	男	180	23.15	—	—	0～1	46，XX
4	46，XY，r(21)(p12q21)	28	28	男	175	25.47	—	—	0～1	46，XX，15p＋
5	46，XY，r(21)(p13q22.3)	29	27	男	170	29.03	—	—	0～1	46，XX
6	46，XY，r(21)(p13q22)	38	41	男	168	21.26	—	—	无精子	46，XX
7	mos46，X，r(Y)(p11q12)[47]/46，X，r(Y；Y)(p11q12；p11q12) [27]/45，X[19]/46，XYqh-[7]	34	29	男	157	20.69	—	—	0～1	46，XX

表1 本组7例环状染色体携带者的临床特征

患者编号	染色体核型^a	年龄(岁)		性别^a	身高^a(cm)	人体质量指数^a(kg/m²)	抗苗勒管激素^a(ng/mL)	窦卵泡计数^a(枚)	精子数^a(个/HP)	配偶染色体核型
患者编号	染色体核型^a	患者	配偶	性别^a	身高^a(cm)	人体质量指数^a(kg/m²)	抗苗勒管激素^a(ng/mL)	窦卵泡计数^a(枚)	精子数^a(个/HP)	配偶染色体核型
1	46，XX，r(7)(p22q36)	26	24	女	143	22.82	1.19	7	—	46，XY
2	mos45，X[52]/46，X，r(X)(p22q27)[48]	28	33	女	150	17.97	<0.06	0	—	46，XY
3	46，XY，r(21)(p11.1q22)	27	24	男	180	23.15	—	—	0～1	46，XX
4	46，XY，r(21)(p12q21)	28	28	男	175	25.47	—	—	0～1	46，XX，15p＋
5	46，XY，r(21)(p13q22.3)	29	27	男	170	29.03	—	—	0～1	46，XX
6	46，XY，r(21)(p13q22)	38	41	男	168	21.26	—	—	无精子	46，XX
7	mos46，X，r(Y)(p11q12)[47]/46，X，r(Y；Y)(p11q12；p11q12) [27]/45，X[19]/46，XYqh-[7]	34	29	男	157	20.69	—	—	0～1	46，XX

表2 本组4例RC携带者PGT-A结果比较[例数(%)]

患者编号	检测囊胚(个)	整倍体胚胎	非整倍体胚胎	嵌合体胚胎	发生于亲缘环状染色体的
非整倍体/嵌合体胚胎^e
患者1-Ⅰ	5	0(0)	5(100.0)	0(0)	5(100.0)
患者1-Ⅱ	6	1(16.7)	2(33.3)	3(50.0)	3(60.0)
患者3-Ⅰ	6	1(16.7)	5(83.3)	0(0)	0(0)
患者3-Ⅱ	6	3(50.0)	2(33.3)	1(16.7)	0(0)
患者5	6	2(33.3)	4(66.7)	0(0)	0(0)
患者7	4	1(25.0)	3(75.0)	0(0)	0(0)
合计(女性/男性)	11/22	1(9.1)/7(31.8)^a	7(63.6)/14(63.6)^b	3(27.3)/1(4.6)^c	8(80.0)/0(0)^d
合计	33	8(24.2)	21(63.6)	4(12.1)	8(32.0)

表2 本组4例RC携带者PGT-A结果比较[例数(%)]

患者编号	检测囊胚(个)	整倍体胚胎	非整倍体胚胎	嵌合体胚胎	发生于亲缘环状染色体的
非整倍体/嵌合体胚胎^e
患者1-Ⅰ	5	0(0)	5(100.0)	0(0)	5(100.0)
患者1-Ⅱ	6	1(16.7)	2(33.3)	3(50.0)	3(60.0)
患者3-Ⅰ	6	1(16.7)	5(83.3)	0(0)	0(0)
患者3-Ⅱ	6	3(50.0)	2(33.3)	1(16.7)	0(0)
患者5	6	2(33.3)	4(66.7)	0(0)	0(0)
患者7	4	1(25.0)	3(75.0)	0(0)	0(0)
合计(女性/男性)	11/22	1(9.1)/7(31.8)^a	7(63.6)/14(63.6)^b	3(27.3)/1(4.6)^c	8(80.0)/0(0)^d
合计	33	8(24.2)	21(63.6)	4(12.1)	8(32.0)

[1]	Pezzolo A, Gimelli G, Cohen A, et al. Presence of telomeric and subtelomeric sequences at the fusion points of ring chromosomes indicates that the ring syndrome is caused by ring instability [J]. Hum Genet, 1993, 92(1): 23-27. DOI: 10.1007/BF00216140.
[2]	Jacobs PA. Mutation rates of structural chromosome rearrangements in man [J]. Am J Hum Genet, 1981, 33(1): 44-54.
[3]	Kosztolányi G. Does " ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosome [J]. Hum Genet, 1987, 75(2): 174-179. DOI: 10.1007/BF00591082.
[4]	Li P, Dupont B, Hu Q, et al. The past, present, and future for constitutional ring chromosomes: a report of the international consortium for human ring chromosomes [J]. HGG Adv, 2022, 3(4): 100139. DOI: 10.1016/j.xhgg.2022.100139.
[5]	Yip MY. Autosomal ring chromosomes in human genetic disorders [J]. Transl Pediatr, 2015, 4(2): 164-174. DOI: 10.3978/j.issn.2224-4336.2015.03.04.
[6]	Cote GB, Katsantoni A, Deligeorgis D. The cytogenetic and clinical implications of a ring chromosome 2 [J]. Ann Genet, 1981, 24(4): 231-235.
[7]	Kosztolányi G, Méhes K, Hook EB. Inherited ring chromosomes: an analysis of published cases [J]. Hum Genet, 1991, 87(3): 320-324. DOI: 10.1007/BF00200912.
[8]	Arnedo N, Nogués C, Bosch M, et al. Mitotic and meiotic behaviour of a naturally transmitted ring Y chromosome: reproductive risk evaluation [J]. Hum Reprod, 2005, 20(2): 462-468. DOI: 10.1093/humrep/deh598.
[9]	Bertini V, Valetto A, Uccelli A, et al. Ring chromosome 21 and reproductive pattern: a familial case and review of the literature [J]. Fertil Steril, 2008, 90(5): 2004. e1-e5. DOI: 10.1016/j.fertnstert.2008.01.087.
[10]	Mantzouratou A, Mania A, Apergi M, et al. Meiotic and mitotic behaviour of a ring/deleted chromosome 22 in human embryos determined by preimplantation genetic diagnosis for a maternal carrier [J]. Mol Cytogenet, 2009, 2: 3. DOI: 10.1186/1755-8166-2-3.
[11]	Cheng D, Yuan S, Yi D, et al. Analysis of molecular cytogenetic features and PGT-SR for two infertile patients with small supernumerary marker chromosomes [J]. J Assist Reprod Genet, 2019, 36(12): 2533-2539. DOI: 10.1007/s10815-019-01611-w.
[12]	陈虹，赵丽娟，刘晓丹，等. 罕见15号环形染色体一例[J].中华医学遗传学杂志，2020, 37(8): 854. DOI: 10.3760/cma.j.issn.1003-9406.2020.08.026，
[13]	陈虹，解洪强，赵丽娟，等. 胚胎植入前遗传学检测技术在环状染色体携带者助孕中的应用价值[J].临床检验杂志，2021，39(4)：257-260. DOI: 10.13602/j.cnki.jcls.2021.04.04.
[14]	Wei D, Liu JY, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial [J]. Lancet, 2019, 393(10178): 1310-1318. DOI: 10.1016/S0140-6736(18)32843-5.
[15]	宋逸，闫晓晋，张京舒，等. 1985－2014年中国汉族18岁青少年身高长期趋势的性别差异变化[J].中华流行病学杂志，2021，42(5)：801-806. DOI: 10.3760/cma.j.cn112338-20200804-01014.
[16]	Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE consensus on the definition of ′poor response′ to ovarian stimulation for in vitro fertilization: the Bologna criteria [J]. Hum Reprod, 2011, 26(7): 1616-1624. DOI: 10.1093/humrep/der092.
[17]	European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, et al. ESHRE guideline: management of women with premature ovarian insufficiency [J]. Hum Reprod, 2016, 31(5): 926-937. DOI: 10.1093/humrep/dew027.
[18]	Yao Q, Wang L, Yao B, et al. Meiotic prophase Ⅰ defects in an oligospermic man with Wolf-Hirschhorn syndrome with ring chromosome 4 [J]. Mol Cytogenet, 2014, 7: 45.
[19]	Zuccarello D, Dallapiccola B, Novelli A, et al. Azoospermia in a man with a constitutional ring 22 chromosome [J]. Eur J Med Genet, 2010, 53(6): 389-391. DOI: 10.1016/j.ejmg.2010.07.014.
[20]	Rajesh H, Freckmann ML, Chapman M. Azoospermia and paternal autosomal ring chromosomes: case report and literature review [J]. Reprod Biomed Online, 2011, 23(4): 466-470. DOI: 10.1016/j.rbmo.2011.05.013.
[21]	Layman LC, Tho SP, Clark AD, et al. Phenotypic spectrum of 45，X/46，XY males with a ring Y chromosome and bilaterally descended testes [J]. Fertil Steril, 2009, 91(3): 791-797. DOI: 10.1016/j.fertnstert.2007.12.078.
[22]	Pristyazhnyuk IE, Menzorov AG. Ring chromosomes: from formation to clinical potential [J]. Protoplasma, 2018, 255(2): 439-449. DOI: 10.1007/s00709-017-1165-1.
[23]	McDermott A, Voyce MA, Romain D. Ring chromosome 4 [J]. J Med Genet, 1977, 14(3): 228-232. DOI: 10.1136/jmg.14.3.228.
[24]	Tian C, Heng D, Zhao N, et al. Short telomeres impede germ cell specification by upregulating MAPK and TGFβ signaling [J]. Sci China Life Sci, 2023, 66(2): 324-339. DOI: 10.1007/s11427-022-2151-0.
[25]	Martínez P, Blasco MA. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins [J]. Nat Rev Cancer, 2011, 11(3): 161-176. DOI: 10.1038/nrc3025.
[26]	Robinson LG Jr, Pimentel R, Wang F, et al. Impaired reproductive function and fertility preservation in a woman with a dyskeratosis congenita [J]. J Assist Reprod Genet, 2020, 37(5): 1221-1225. DOI: 10.1007/s10815-020-01758-x.
[27]	Dai K, Xu H, Ouyang N, et al. Correlation of human telomerase reverse transcriptase single nucleotide polymorphisms with in vitro fertilisation outcomes [J]. J Assist Reprod Genet, 2019, 36(3): 517-527. DOI: 10.1007/s10815-018-1379-y.
[28]	Surace C, Berardinelli F, Masotti A, et al. Telomere shortening and telomere position effect in mild ring 17 syndrome [J]. Epigenet Chromatin, 2014, 7(1): 1. DOI: 10.1186/1756-8935-7-1.
[29]	Chauhan P, Jaiswal SK, Lakhotia AR, et al. Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome [J]. J Assist Reprod Genet, 2016, 33(9): 1161-1168. DOI: 10.1007/s10815-016-0761-x.
[30]	László J, Gaál M, Bósze P. Nonmosaic 46，X，r(Y) karyotype with female phenotype [J]. Hum Genet, 1977, 38(3): 351-356. DOI: 10.1007/BF00402164.
[31]	Portuondo JA, Barral A, Neyro JL, et al. Gonadal dysgenesis and somatic stigmata in patients with 45，X/46, Xr(X) ring chromosome [J]. Int J Gynaecol Obstet, 1984, 22(4): 311-313. DOI: 10.1016/0020-7292(84)90089-4.
[32]	Spinner NB, Saitta SC, Delaney DP, et al. Intracytoplasmic sperm injection (ICSI) with transmission of a ring(Y) chromosome and ovotesticular disorder of sex development in offspring [J]. Am J Med Genet A, 2008, 146A(14): 1828-1831. DOI: 10.1002/ajmg.a.32358.
[33]	Tulloch WS, Newsam JE. Studies on human meiotic chromosomes from testicular tissue [J]. Lancet, 1966, 1(7439): 679-682. DOI: 10.1016/s0140-6736(66)91627-8.
[34]	Portuondo JA, Barral A, Neyro JL, et al. Gonadal dysgenesis and somatic stigmata in patients with 45，X/46，Xr(X) ring chromosome [J]. Int J Gynaecol Obstet, 1984, 22(4): 311-313. DOI: 10.1016/0020-7292(84)90089-4.
[35]	Hammoud I, Gomes DM, Bergere M, et al. Sperm chromosome analysis of an infertile patient with a 95% mosaic r(21) karyotype and normal phenotype [J]. Fertil Steril, 2009, 91(3): 930. e13-e15. DOI: 10.1016/j.fertnstert.2008.12.005.
[36]	Lane S, Kauppi L. Meiotic spindle assembly checkpoint and aneuploidy in males versus females [J]. Cell Mol Life Sci, 2019, 76(6): 1135-1150. DOI: 10.1007/s00018-018-2986-6.
[37]	李晨曦，党玉洁，秦莹莹. 特纳综合征患者生育力相关问题的研究进展[J].中华妇产科杂志，2021, 56(1): 73-76. DOI: 10.3760/cma.j.cn112141-20200610-00491.
[38]	Melnyk AR, Ahmed I, Taylor JC. Prenatal diagnosis of familial ring 21 chromosome [J]. Prenat Diagn, 1995, 15(3): 269-273. DOI: 10.1002/pd.1970150310.

[1]	Jiaxuan Liu, Binghe Xu. Annual advancement of clinical research on breast cancer in China[J]. Chinese Journal of Breast Disease(Electronic Edition), 2023, 17(05): 259-265.
[2]	Jun Wang, Zhenqiang Zhang, Xiyi Wang, Xingqing Gou, Yuping He. Analysis of influencing factors on results of embryo preimplantation genetic testing for chromosome structural rearrangement in chromosomal reciprocal translocation carriers[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2022, 18(06): 652-659.
[3]	Wanting Cui, Yanyan Zhao. Current research status on chromosomal mosaicism and uniparental disomy[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2022, 18(02): 132-138.
[4]	Aiqi Cai, Jinman Zhang, Xinhua Tang, Baosheng Zhu. Prenatal diagnosis and genetic counseling of fetal copy number variation[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2021, 17(03): 262-267.
[5]	Yupei Zhao, Jiangdong Qiu. The laparoscopic radical surgery for pancreatic cancer in China: Review and prospect in 20 years[J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Edition), 2021, 15(03): 237-240.
[6]	Jun Wu, Lixuan Chen, Yang Xiao. Analysis of dual filing research projects on stem cells in China[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(05): 304-309.
[7]	Hongmin Wang, Yunbo Xie, Yanhu Wang, Fusheng Wang. The advance of clinical research in mesenchymal stem cell treatment for COVID-19[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 247-256.
[8]	Qi'ao Yu, Huan Song, Xiaodong Wang, Li Li. Application of UK Biobank in clinical research of colorectal neoplasm[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2021, 10(04): 351-356.
[9]	Guoliang Wu, Li Li. Clinical study on the treatment of rectal mucosal prolapse constipation by constipation cream retention enema[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2021, 10(03): 255-259.
[10]	Jiafa Ren, Buyun Wu, Changying Xing, Huijuan Mao. Advances in the basic and clinical research on acute kidney injury in 2022[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2023, 12(05): 276-281.
[11]	Ting Li, Ling Jiang, Luhan Geng, Zhimin Huang, Yanggang Yuan, Bo Zhang, Ningning Wang, Li Zhang, Huijuan Mao, Changying Xing. Update on clinical research on nephrology in 2021[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2022, 11(02): 84-89.
[12]	Buyun Wu, Xueqiang Xu, Changying Xing, Huijuan Mao. Advances in the clinical research on blood purification in 2020[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2021, 10(01): 20-24.
[13]	Yinghong Lin, Yupeng Zhang, Jinyan Xia, Li Huang, Zuanfang Li, Kunzhe Lin, Shousen Wang. Registration analysis of traumatic brain injury related clinical trials on Chinese Clinical Trial Registry[J]. Chinese Journal of Brain Diseases and Rehabilitation(Electronic Edition), 2022, 12(02): 74-80.
[14]	Jingda Zheng, Jinqi Huang, Qingxian Zhang, Huang Chen, Xiaojie Gao. Clinical study of AngioJet one-stop thrombectomy via deep lower leg vein approach in patients with acute lower limb deep vein thrombosis[J]. Chinese Journal of Interventional Radiology(Electronic Edition), 2023, 11(04): 305-309.
[15]	Yining Shen, Shijin Zhou, Meng Yu, Pingping An, Cong Wu. Application prospect of new technologies in the era of big data in clinical databases[J]. Chinese Journal of Clinical Laboratory Management(Electronic Edition), 2023, 11(02): 109-113.

Viewed

Full text

Abstract

Please choose a citation manager

Content to export