GENETICS AND INFERTILITY

The genetic sex of an embryo is determined at the moment of conception when a sperm and egg unite. The union of the egg and sperm results in an embryo with 46 chromosomes consisting of 22 pairs of chromosomes (numbered 1 to 22) and two sex chromosomes. The chromosomes are made up of many thousands of genes that determine how the body functions, survives and reproduces. In humans and other mammals females have two sex chromosomes (written as XX) whereas males have a single X chromosome and a single Y sex chromosome (XY). It is the presence of the Y chromosome that directs the gonads in an embryo to transform into testes that once formed, produce the hormones necessary for development into a male.

Abnormalities in chromosome number and structure are associated with infertility (see below), congenital malformations and mental retardation. Chromosome abnormalities occur in six per thousand infants born and are very common in spontaneous abortions, representing about 50% of the conceptions that are lost spontaneously. The incidence of chromosomal abnormalities increases with the age of the mother.

MATERNAL AGE AND THE INCIDENCE OF CHROMOSOME ABNORMALITIES

Chromosomal disorders are incurable but can be detected by prenatal diagnostic techniques such as amniocentesis or chorionic villous sampling. Chromosomal abnormalities can also be detected in an embryo by a technique known as preimplantation genetic diagnosis (PGD). In this technique embryos are grown in vitro and a single cell removed for chromosomal analysis. Removing a cell from the embryo at an early stage (day 3) can be done without being detrimental to future embryonic growth. The advantage of PGD is that it allows a chromosomally normal embryo to be transplanted into the uterus.

COMMON CHROMOSOME ABNORMALITIES

CHROMOSOME ABNORMALITIES THAT CAUSE INFERTILITY

Chromosome abnormalities causing infertility can be due to an inappropriate number of chromosomes, to chromosome damage or to undesirable changes in chromosome structure (missing genes - mutations).

Research has shown that chromosome abnormalities are directly related to the number of sperm present in a semen sample and occur in around 5% of infertile men. The most common chromosome abnormality that results in male infertility is Klinefelter’s syndrome. Men with this abnormality have an extra X chromosome (XXY). The frequency of Klinefelter’s syndrome in infertile men is 40% higher than in the general population. It is estimated that abnormalities in chromosome number occur in 5 to 10% of infertile women with Turner’s syndrome (XO) one of the most well known. The most common features of this syndrome are short stature and infertility.

In situations where the number of chromosomes is correct, infertility can occur because some of the genes on a particular chromosome are missing. These abnormalities are called genetic mutations. Cystic fibrosis is an example of a mutation that causes infertility in male sufferers. The infertility is due to the absence of the vas deferens (tube that transports sperm from the testes) leading to obstructive azoospermia (no sperm in semen) in otherwise healthy males. In cases of absent vas deferens sperm can be obtained by surgical means from the epididymis (sperm storage area) or directly from the testis and used in assisted reproduction via the ICSI (intracytoplasmic sperm injection) procedure.

It is now well known that missing genes (mircodeletions) on the Y chromosome are related to male infertility. Over the last 5 years there has been a vast number of clinical and molecular research studies into the Y chromosome. The reported frequency of Y chromosome microdeletions in infertile men ranges from 1 to 55 %. Y chromosome microdeletions have been seen almost exclusively in men who are oligozoospermic (low sperm count) or azoospermic. Large follow up studies have shown an increased risk of transmitting Y chromosome mircrodeletions from father to son following the ICSI procedure.

Mutation of the male hormone (androgen) receptor can also cause infertility. The prevalence of this abnormality is still unknown but believed to be quite rare. Effected men have normal genitals but have very poor sperm quality with severely low sperm counts and a high incidence of abnormally formed sperm.

GENETIC TESTING

A range of highly complex laboratory tests have been developed to identify genetic defects. Tests are available to identify abnormalities in chromosome number, gene mutations and DNA damage in sperm. Men with oligospermia (very low sperm count) or azoospermia (no sperm) are advised to seek genetic counseling and testing before undergoing assisted reproductive procedures such as ICSI.