The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, New York.
The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, New York.
Fertil Steril. 2023 Feb;119(2):196-206. doi: 10.1016/j.fertnstert.2022.11.006. Epub 2022 Nov 12.
To identify specific germline mutations related to sperm reproductive competence, in couples with unexplained infertility.
In this retrospective study, couples were divided according to whether they had successful intracytoplasmic sperm injection outcomes (fertile) or not (infertile). Ancillary sperm function tests were performed on ejaculates, and whole exome sequencing was performed on spermatozoal DNA. Sperm aneuploidy and gene mutation profiles were compared between the 2 cohorts as well as according to the specific reasons for reproductive failure.
Center for reproductive medicine at a major academic medical center.
PATIENT(S): Thirty-one couples with negative infertility workups and normal semen parameters.
INTERVENTION(S): Couples with mutations on fertilization- or embryo development-related genes were subsequently treated by assisted gamete treatment or microfluidics, respectively.
MAIN OUTCOME MEASURE(S): Intracytoplasmic sperm injection cycle outcomes including fertilization, clinical pregnancy, and delivery rates.
RESULT(S): Sperm aneuploidy was lower in the fertile group (4.0% vs. 8.4%). Spermatozoa from both cohorts displayed mutations associated with sperm-egg fusion (ADAM3A) and acrosomal development (SPACA1), regardless of reproductive outcome. The infertile cohort was then categorized according to the reasons for reproductive failure: absent fertilization, poor early embryo development, implantation failure, or pregnancy loss. Spermatozoa from the fertilization failure subgroup (n = 4) had negligible PLCζ presence (10% ± 9%) and gene mutations (PLCZ1, PIWIL1, ADAM15) indicating a sperm-related oocyte-activating deficiency. These couples were successfully treated by assisted gamete treatment in their subsequent cycles. Spermatozoa from the poor early embryo development subgroup (n = 5) had abnormal centrosomes (45.9% ± 5%), and displayed mutations impacting centrosome integrity (HAUS1) and spindle/microtubular stabilization (KIF4A, XRN1). Microfluidic sperm processing subsequently yielded a term pregnancy. Spermatozoa from the implantation failure subgroup (n = 7) also had abnormal centrosomes (53.1% ± 13%) and carried mutations affecting embryonic implantation (IL9R) and microtubule and centrosomal integrity (MAP1S, SUPT5H, PLK4), whereas those from the pregnancy loss subgroup (n = 5) displayed mutations on genes involved in trophoblast development (NLRP7), cell cycle regulation (MARK4, TRIP13, DAB2IP, KIF1C), and recurrent miscarriage (TP53).
CONCLUSION(S): By assessing the sperm genome, we identified specific germline mutations related to various reproductive processes. This information may clarify elusive factors underlying reproductive competence and enhance treatment for couples with unexplained infertility.
鉴定与不明原因不孕夫妇精子生殖能力相关的特定种系突变。
在这项回顾性研究中，根据是否有成功的胞浆内单精子注射结局（有生育能力）将夫妇分为两组。对精液进行辅助精子功能检测，并对精子 DNA 进行全外显子组测序。比较了两组之间以及根据生殖失败的具体原因的精子非整倍体和基因突变谱。
主要学术医疗中心的生殖医学中心。
31 对不孕检查阴性且精液参数正常的夫妇。
具有受精或胚胎发育相关基因突变的夫妇随后分别接受辅助配子治疗或微流控处理。
胞浆内单精子注射周期结局包括受精、临床妊娠和分娩率。
有生育能力组的精子非整倍体率较低（4.0%对 8.4%）。两组的精子均显示与精子-卵子融合（ADAM3A）和顶体发育（SPACA1）相关的突变，无论生殖结局如何。然后根据生殖失败的原因将不孕组进一步分类：无受精、早期胚胎发育不良、着床失败或妊娠丢失。受精失败亚组（n=4）的精子 PLCζ 存在率（10%±9%）和基因突变（PLCZ1、PIWIL1、ADAM15）可忽略不计，表明精子相关的卵激活缺陷。这些夫妇在随后的周期中通过辅助配子治疗成功治疗。早期胚胎发育不良亚组（n=5）的精子有异常中心体（45.9%±5%），并显示影响中心体完整性（HAUS1）和纺锤体/微管稳定（KIF4A、XRN1）的基因突变。随后的微流控精子处理产生了一个足月妊娠。着床失败亚组（n=7）的精子也有异常中心体（53.1%±13%），并携带影响胚胎着床的基因突变（IL9R）和微管及中心体完整性的基因突变（MAP1S、SUPT5H、PLK4），而妊娠丢失亚组（n=5）则显示参与滋养层发育的基因（NLRP7）、细胞周期调节（MARK4、TRIP13、DAB2IP、KIF1C）和复发性流产（TP53）的基因突变。
通过评估精子基因组，我们鉴定了与各种生殖过程相关的特定种系突变。这些信息可以阐明生殖能力背后难以捉摸的因素，并为不明原因不孕夫妇提供增强的治疗。
