In recent years, the incidence of infertility has gradually increased, and studies have shown that male factors account for about 50% of the causes of infertility and are related to sperm quantity and quality [4]. The acrosome is a lysosome-associated organelle unique to spermatozoa, located in the head of the spermatozoa, which contains a variety of soluble hydrolytic enzymes necessary for penetration of the oocyte, such as acrosomal enzymes, hyaluronidase, etc. and insoluble matrix molecules, which play an important role in the fertilization process [5]. Therefore, abnormal acrosomal structure and reduced acrosomal enzyme activity prevent sperm from crossing the zona pellucida and binding to the oocyte, leading to infertility,results as shown.
Pathogenic variants in the genes PICK1, SPATA16 and DPY19L2 have been shown to cause complete acrosomal deletion and round head spermatidosis in human spermatozoa3, 6. DPY19L2, a member of the DPY19 gene family, is a transmembrane protein expressed specifically in the testis and is formed by the duplication of DPY19L1 located on chromosome 7 and then re-located on chromosome 12. It contains 22 exons connecting the sperm acrosomal membrane to the nuclear membrane, and deletion of DPY19L2 protein expression results in separation of the sperm acrosome from the nucleus during the sperm deformation stage, leading to disruption of vesicle transport, failure of the sperm nucleus to take shape, elimination of unbound acrosomal vesicles, and ultimately the production of acrosomal-less round-headed spermatozoa7–8. The routine whole exome testing in this case suggested the mutant locus of the DPY19L2 gene, which resulted in the sperm acrosome defect in this male, and this assertion was laterally corroborated by exome sequencing of the family line confirming the pure mutation of DPY19L2c.63dupG (p.Arg22Alafs*66). Patients with acrosomal structural defects have no other characteristic clinical manifestations compared to the normal population. The main manifestation was male infertility with decreased sperm motility compared to normal fertile men. In our case, the sperm viability was slightly lower than that of normal patients, and the acrosomal enzyme concentration and total number were not significantly different from those of the normal population, which is consistent with those reported in the relevant literature9–10. Patients with acrosomal structural defects are currently considered to have ICSI as the method of choice for their offspring due to low fertility or even inability to have children naturally, but the fertilization rate is low and the failure rate of complete fertilization is high, which may be due to the failure of egg activation. In recent years, the proposed ICSI combined with artificial oocyte activation (AOA) technique helps to improve the fertilization rate of oocytes, which is suitable for patients with low fertilization rate or even complete failure, but there are still some patients with complete fertilization failure11.
Pure mutation in the DPY19L2 gene is the main cause of roundhead spermatosis, and the success of such patients in obtaining clinical pregnancies and producing offspring by performing ICSI has been reported both at home and abroad, but the majority of the cases were carriers of the mutation in this gene12–13. In the study, it was found that patients of this family line presented typical mutation results, and the result of insertion mutation directly led to the mutation of amino acid 22 from arg to ala, and the downstream protein structure was typically mutated. It has been shown that more than dozens of mutation patterns have been reported in the DPY19L2 gene, and new mutation patterns are constantly being discovered, but our discovery of this mutation is the first report, which enriches the evidence for the study of the pathogenicity of this gene in roundhead spermatosis.
Of interest is the history of consanguineous marriage in the family of our patient, with the patient's grandparents and parents being consanguineous and her parents being heterozygous carriers of the DPY19L2 mutation. Genetics has shown that offspring of consanguineous marriages have a higher probability of developing genetic diseases than offspring of non-consanguineous marriages, and that consanguineous marriages increase the probability of prenatal fetal death14. Phenotypically normal humans may carry multiple recessive disease-causing genes, and consanguineous relatives are likely to have the same recessive disease-causing genes. When the genes are heterozygous, the dominant genes are expressed in normal traits, the recessive genes are not expressed, and the human body behaves normally; consanguineous marriages increase the level of purity in the recessive disease-causing genes of the offspring, and they express the disease-causing traits, i.e., the genetic disease15. In our case, the offspring born after ICSI-assisted conception was born with congenital cardiac malformation and died 6 days after birth, and it was hypothesized that the causative cause of the disease might be related to consanguineous marriage.
The DPY19L2 gene mutation in spherospermia is a biallelic gene mutation, and the genetic mode of this gene is likely to be recessive homozygous pathogenic. Therefore, in the reproductive clinic, normal carriers will not show infertility induced by spherospermia. The main pathogenic risk of this gene is that the wife as a carrier leads to homozygous infertility in male offspring.