Risk of transmission of genetic diseases by assisted reproduction

Abstract

Infertility devastates the life plans of 8%-12% of couples attempting to conceive for the first time. In about half of these cases a male factor is causative. Interestingly, research in male reproduction over the past 30 years has focused largely on the endocrine control of spermatogenesis and genital tract function, yet only about 1% of male infertility has an endocrine cause; thus, this research has had little effect on the treatment of the infertile male. With advancements in molecular medicine, researchers are now beginning to dissect the genes required for male fertility, although their approaches predominantly take advantage of ever-expanding collections of mouse models. 1 The advent of surgical sperm collection from the epididymis or testis and the development of intracytoplasmic sperm injection (ICSI) have provided the only major technological advances in recent years.While most textbooks state that approximately 30% of male infertility is idiopathic, some experts speculate that perhaps 50% of all male infertility is idiopathic. In part, this speculation reflects our poor understanding of the basic mechanisms that regulate genital tract differentiation and development, spermatogenesis, sperm maturation in the genital tract, and the molecular events required for fertilization and early embryonic development; and, hence, our inability to properly diagnose the cause of the infertility. Indeed, commonly used diagnostic categories for male infertility are descriptive and not usually mechanistically based. Accordingly, our ability to properly diagnose and counsel male factor infertile couples is limited. Nevertheless, research shows that genetic defects in male factor infertility are more common than originally believed. These findings have raised concerns that since the assisted reproductive technologies essentially overcome the natural barriers to defective sperm fertilization, mechanisms may now be bypassed that prevent the transmission of genetic defects to offspring of these genetically infertile men.Recognizing this diagnostic limitation, there are nevertheless important clinical genetic tests that should be used today in the diagnosis of the infertile male. The karyotype remains the gold standard of chromosomal analysis and provides important insights regarding the presence of both numerical and structural chromosome abnormalities. Although chromosomal abnormalities are uncommon in fertile men, routine karyotyping suggests that these abnormalities are present in about 6% of infertile men. 2 Defects include human trisomies that result from aberrant recombination during gametogenesis such as sex chromosome abnormalities, which are among the most common human trisomies. 3 For

Comprehensive 5-Year Study of Cytogenetic Aberrations in 668 Infertile Men

“…Investigators estimate that almost 50% of patients with idiopathic male infertility have a genetic contribution but most of these genetic factors remain to be elucidated. To date specific genetic defects, including chromosomal aberrations and gene defects, ie sex chromosome aneuploidy and cystic fibrosis mutation, have been identified in fewer than 20% of male patients with infertility 8. Recent reports of genetic defects associated with abnormal semen parameters, such as SYCP3, PRM1, KLHL10, SPATA16 and AURKC , lack epidemiological data 9–14.…”

“…415000 of the National Center for Biotechnology Information 15,16. Of male infertility cases aneuploidy of sex chromosomes such as 47,XXY, ie Klinefelter syndrome, accounts for up to 3% and structural rearrangements involving X and/or Y chromosomes account for an estimated 1% to 3% 8,17. Less commonly OS and AS are associated with numerical or structural autosomal abnormalities 6,18.…”

Chromosomal abnormalities in patients with infertility

“…ART utilization, espe cially intracytoplasmic sperm injection, bypasses this natural barrier to fertilization, increasing the risk of 1 The article was translated by the authors. transmission of chromosomal abnormalities to the off spring [11,12]. Since chromosomal abnormalities in patients with infertility usually do not manifest pheno typically (balanced structural rearrangements, mosaic or non mosaic forms of sex chromosome aneup loidies, additional marker chromosomes), the cytoge netic investigation before ART is of crucial impor tance for the detection of chromosomal abnormalities and prevention of their transmission to the offspring.…”

High Quality RNA in Semen and Sperm: Isolation, Analysis and Potential Application in Clinical Testing

“…3 Although sperm abnormalities are common in infertile men, almost 50% of patients are diagnosed with idiopathic infertility to which genetic factors are likely contributors. 4,5 More than 3,000 genes are expressed in the male reproductive system and more than 500 animal knockout models were reported with male infertility. 6–8 Progress in understanding human infertility is limited due to its clinical and genetic heterogeneity.…”