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中华妇幼临床医学杂志(电子版) ›› 2024, Vol. 20 ›› Issue (01) : 58 -64. doi: 10.3877/cma.j.issn.1673-5250.2024.01.008

论著

环状染色体携带者助孕结局分析
冯晨1, 郑英2, 武童1, 李敬3, 夏铭笛3, 鲁娟娟3, 党玉洁4,†()   
  1. 1. 山东大学生殖医学研究中心，国家辅助生殖与优生工程技术研究中心，生殖内分泌教育部重点实验室，山东省生殖健康临床医学研究中心，济南　250012
    2. 滕州市工人医院门诊手术室，滕州　277500
    3. 山东大学生殖医学研究中心，国家辅助生殖与优生工程技术研究中心，生殖内分泌教育部重点实验室，山东省生殖健康临床医学研究中心，济南　250012；山东大学附属生殖医院生殖遗传科，济南　250012
    4. 山东大学生殖医学研究中心，国家辅助生殖与优生工程技术研究中心，生殖内分泌教育部重点实验室，山东省生殖健康临床医学研究中心，济南　250012；山东大学附属生殖医院女性生殖科，济南　250012
  • 收稿日期:2023-07-11 修回日期:2024-01-05 出版日期:2024-02-01
  • 通信作者: 党玉洁

Analysis of assisted pregnancy outcomes of ring chromosome carriers

Chen Feng1, Ying Zheng2, Tong Wu1, Jing Li3, Mindi Xia3, Juanjuan Lu3, Yujie Dang4,†()   

  1. 1. Center for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong Province, China
    2. Department of Out-Patient Operating Room, Tengzhou Workers′ Hospital, Tengzhou 277500, Shandong Province, China
    3. Center for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong Province, China; Department of Reproductive Genetics, Reproductive Hospital Affiliated to Shandong University, Jinan 250012, Shandong Province, China
    4. Center for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong Province, China; Department of Female Reproduction, Reproductive Hospital Affiliated to Shandong University, Jinan 250012, Shandong Province, China
  • Received:2023-07-11 Revised:2024-01-05 Published:2024-02-01
  • Corresponding author: Yujie Dang
  • Supported by:
    National Natural Science Foundation of China(81701406); Natural Science Foundation of Shandong Province(ZR2022MH009)
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引用本文：

冯晨, 郑英, 武童, 李敬, 夏铭笛, 鲁娟娟, 党玉洁. 环状染色体携带者助孕结局分析[J]. 中华妇幼临床医学杂志(电子版), 2024, 20(01): 58-64.

Chen Feng, Ying Zheng, Tong Wu, Jing Li, Mindi Xia, Juanjuan Lu, Yujie Dang. Analysis of assisted pregnancy outcomes of ring chromosome carriers[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2024, 20(01): 58-64.

目的

探讨环状染色体(RC)携带者的助孕结局。

方法

选择2014年3月至2022年4月于山东大学附属生殖医院进行辅助生殖助孕的7例RC携带者(患者1～7)为研究对象。对这7例RC携带者的临床特征、妊娠结局及胚胎植入前非整倍体遗传学检测(PGT-A)的胚胎整倍体率进行统计学分析。本研究遵循的程序符合山东大学附属生殖医院医学伦理委员会要求，并获取批准[审批文号：〔2021〕论审字(130)号]，所有患者签署临床研究知情同意书。

结果

①患者1、2为女性，患者1为常染色体RC携带者，出现卵巢储备功能下降；患者2为RC X嵌合体携带者，确诊早发性卵巢功能不全(POI)。患者3～7为男性，4例(患者3～6)为常染色体RC携带者，1例(患者7)为RC Y嵌合体携带者，均表现为严重少精子症或无精子症。②4例携带者(患者1、3、5、7)进行PGT-A，共检测胚胎33枚，其中整倍体胚胎8枚(24.2%)，非整倍体胚胎21枚(63.6%)，嵌合体胚胎4枚(12.1%)，发生于亲缘环状染色体的非整倍体/嵌合体胚胎占32.0%(8/25)。男、女性RC携带者胚胎整倍体率比较，差异无统计学意义(P>0.05)，但是女性RC携带者亲缘环状染色体非整倍体/嵌合体胚胎发生风险，显著高于男性RC携带者(P<0.001)。③对4例携带者(患者2、4、6、7)进行供卵或供精助孕。

结论

RC携带者胚胎整倍体率低，其中女性RC携带者尤甚；RC携带者进行PGT-A筛选整倍体胚胎，能够降低胚胎因素导致的不良妊娠风险。男性发生21号染色体环状染色体，均表现为严重少弱畸形精子症，甚至无精子症，提示21号染色体空间结构改变或破坏，可能影响并参与精子发生的关键基因的功能，具体机制有待进一步研究。

关键词: 环状染色体, 胚胎植入前遗传学检测, 遗传咨询, 临床研究
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 配偶
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)
[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.
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