Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa

Infertility and pregnancy loss are longstanding problems. Successful fertilization and high-quality embryos are prerequisites for an ongoing pregnancy. Studies have proven that every stage in the human reproductive process is regulated by multiple genes and any problem, at any step, may lead to fertilization failure (FF) or early embryonic arrest (EEA). Doctors can diagnose the pathogenic factors involved in FF and EEA by using genetic methods. With the progress in the development of new genetic technologies, such as single-cell RNA analysis and whole-exome sequencing, a new approach has opened up for us to directly study human germ cells and reproductive development. These findings will help us to identify the unique mechanism(s) that leads to FF and EEA in order to find potential treatments. The goal of this review is to compile current genetic knowledge related to FF and EEA, clarifying the mechanisms involved and providing clues for clinical diagnosis and treatment. PubMed was used to search for relevant research articles and reviews, primarily focusing on English-language publications from January 1978 to June 2023. The search terms included fertilization failure, early embryonic arrest, genetic, epigenetic, whole-exome sequencing, DNA methylation, chromosome, non-coding RNA, and other related keywords. Additional studies were identified by searching reference lists. This review primarily focuses on research conducted in humans. However, it also incorporates relevant data from animal models when applicable. The results were presented descriptively, and individual study quality was not assessed. A total of 233 relevant articles were included in the final review, from 3925 records identified initially. The review provides an overview of genetic factors and mechanisms involved in the human reproductive process. The genetic mutations and other genetic mechanisms of FF and EEA were systematically reviewed, for example, globozoospermia, oocyte activation failure, maternal effect gene mutations, zygotic genome activation abnormalities, chromosome abnormalities, and epigenetic abnormalities. Additionally, the review summarizes progress in treatments for different gene defects, offering new insights for clinical diagnosis and treatment. The information provided in this review will facilitate the development of more accurate molecular screening tools for diagnosing infertility using genetic markers and networks in human reproductive development. The findings will also help guide clinical practice by identifying appropriate interventions based on specific gene mutations. For example, when an individual has obvious gene mutations related to FF, ICSI is recommended instead of IVF. However, in the case of genetic defects such as phospholipase C zeta1 (PLCZ1), actin-like7A (ACTL7A), actin-like 9 (ACTL9), and IQ motif-containing N (IQCN), ICSI may also fail to fertilize. We can consider artificial oocyte activation technology with ICSI to improve fertilization rate and reduce monetary and time costs. In the future, fertility is expected to be improved or restored by interfering with or supplementing the relevant genes. Identifying the unique genetic mechanisms underlying fertilization failure and early embryo arrest can facilitate the discovery of potential therapeutic approaches (created using Figdraw). ACTL7A, actin-like7A; ACTL9, actin-like 9; BTG4, B-cell anti-proliferation factor 4; CDC20, cell division cycle 20; CHEK1, checkpoint kinase 1; circRNA, circular RNA; cRNA, complementary RNA; H3K4me3, trimethylation of histone H3 lysine 4; H3K9me3, trimethylation of histone H3 lysine 9; H3K27me3, trimethylation of histone H3 lysine 27; IQCN, IQ motif-containing N; KHDC3L, KH domain containing 3 like; lncRNA, long ncRNA; miRNA, microRNA; NLRP2, NLR family pyrin domain containing 2; NLRP5, NLR family pyrin domain containing 5; NLRP7, NLR family pyrin domain containing 7; OOEP, oocyte expressed protein; PADI6, peptidyl arginine deiminase 6; piRNA, PIWI interacting RNA; PLCZ1, phospholipase C zeta1; TLE6, TLE family member 6; TUBA4A, tubulin alpha 4a; TUBB8, tubulin beta 8 class VIII; WEE2, WEE2 oocyte meiosis inhibiting kinase; ZP, zona pellucida glycoprotein.

Kartagener's syndrome (KS) is an autosomal recessive genetic disease accounting for approximately 50% of the cases of primary ciliary dyskinesia (PCD). As it is accompanied by many complications, PCD/KS severely affects the patient's quality of life. Therapeutic approaches for PCD/KS aim to enhance prevention, facilitate rapid definitive diagnosis, avoid misdiagnosis, maintain active treatment, control infection and postpone the development of lesions. In male patients, sperm flagella may show impairment in or complete absence of the ability to swing, which ultimately results in male infertility. Assisted reproductive technology will certainly benefit such patients. For PCD/KS patients with completely immotile sperm, intracytoplasmic sperm injection may be very important and even indispensable. Considering the number of PCD/KS susceptibility genes and mutations that are being identified, more extensive genetic screening is indispensable in patients with these diseases. Moreover, further studies into the potential molecular mechanisms of these diseases are required. In this review, we summarize the available information on various aspects of this disease in order to delineate the therapeutic objectives more clearly, and clarify the efficacy of assisted reproductive technology as a means of treatment for patients with PCD/KS-associated infertility.