about aneuploidy
Frequently Asked Questions About Chromosomes and Aneuploidy
What is a chromosome abnormality or 'aneuploidy'? 
Aneuploidy is a term used to describe an abnormal number of chromosomes. Chromosomes are structures in each cell of our body that carry our genetic information, or genes, in the form of DNA.
Healthy humans normally have 46 chromosomes arranged in pairs: 22 pairs of ‘autosomes’ (numbered from 1 to 22) and one pair of ‘sex chromosomes’ (XX in females or XY in males). Thus, humans have a total of 24 different types of chromosomes (1-22, X, Y).
How are chromosomes inherited? A child receives one of each pair of chromosomes from the mother in the egg and one of each pair from the father in the sperm. Normally, the egg and the sperm each have 23 chromosomes so that the first cell of the child has a total of 46 chromosomes – half from the mother and half from the father.
Sometimes during the formation of the egg or sperm an error can occur, resulting in an egg or sperm with an abnormal number of chromosomes. This type of error is called 'chromosome non-disjunction'. The result is aneuploidy in the embryo. Having an extra chromosome is called 'trisomy'; a missing chromosome is called 'monosomy'.
The vast majority of embryos with aneuploidy do not implant in the uterus or are lost in early miscarriage often before a woman even realizes she's been pregnant. In fact, over half of all early miscarriages are due to aneuploidy. In some cases a baby can be born with an abnormal number of chromosomes, a situation usually associated with mental retardation and birth defects. The specific features found in a baby with aneuploidy depend on which chromosome is extra or missing. An example of a common type of aneuploidy is Down syndrome, caused by three copies of chromosome number 21 (Trisomy 21).
Some of the more common aneuploidy conditions that can occur in live born babies include:
Trisomy 21 (Down syndrome)
Down syndrome, or Trisomy 21, caused by an extra chromosome of the 21st pair, accounts for about half of chromosome abnormalities found in live born babies. Children with Down syndrome have characteristic facial features that most people recognize. Most children are mentally retarded with an average IQ of about 50, although this varies from person to person. The average life span of a person with Down syndrome is between 35 and 50 years.
Trisomy 18Trisomy 18, also called Edward syndrome, is caused by three copies of chromosome 18. The extra chromosome causes multiple severe birth defects including structural abnormalities of the brain, heart, kidneys and genitals. Most babies with Trisomy 18 are stillborn or die shortly after birth due to the severe brain and heart malformations.
Trisomy 13Trisomy 13, also called Patau syndrome, is caused by an extra copy of chromosome 13. Babies with Trisomy 13 have multiple severe birth defects of the brain, heart, kidneys, gastrointestinal tract and genitals. Most fetuses with trisomy 13 are lost in miscarriage, are stillborn, or die shortly after birth.
Klinefelter Syndrome (XXY)Klinefelter syndrome, also known as XXY, affects between 1 in 500 and 1 in 1,000 males. Boys with Klinefelter syndrome may have learning disabilities and difficulty with speech and language development. Most have low levels of testosterone during puberty which can lead to breast development (gynecomastia), reduced facial and body hair, and infertility. Testosterone replacement therapy starting at puberty can prevent many of these features, but the infertility is usually permanent.
Turner Syndrome (XO)Turner syndrome, also known as 45,XO, or “XO”, is caused by a missing sex chromosome. Turner syndrome occurs in about 1 in 2500 to 1 in 5000 female births. The rate of XO in embryos is much higher than this and nearly 99% of embryos with XO are lost in miscarriage early in pregnancy. Most girls with Turner syndrome have short stature, are infertile and do not develop secondary sex characteristics without hormone replacement. Some have more serious birth defects of the heart or kidneys. Most girls are of average intelligence, although many have specific learning disabilities and may need additional help in school.
XXX (Triple X syndrome)47,XXX, also known as XXX or Triple X, affects about one in every thousand females. Most females with XXX do not look different in appearance but are often taller than average and may have minor coordination problems. Most girls are of average intelligence, although they are at increased risk for learning difficulties, speech and language delays, and behavioral and emotional problems to varying degrees. Women with XXX typically have normal fertility.
XYY (Jacob syndrome) 47, XYY, also known as XYY or Jacob syndrome, affects about one in every thousand males. Most males with XYY do not look different in appearance, although they may be taller than average. Most boys are of average intelligence although they are at increased risk for learning disabilities, speech and language delays, and behavior problems to varying degrees. Men with XYY typically have normal fertility.
What is the chance of aneuploidy? Aneuploidy can happen in any pregnancy just by a chance error in the formation of the sperm or egg, or early during embryo development, resulting in too few or too many chromosomes in the embryo. Although anyone can have an embryo with aneuploidy, the chance increases with the age of the mother. Additionally, due to the fact that the majority of fetuses with aneuploidy miscarry, the chance of aneuploidy is higher if testing an embryo, and decreases when testing a fetus (during the pregnancy), or a newborn baby.
About 1 in every 500 live born babies has some type of chromosome abnormality. The rate of aneuploidy in embryos is much higher, reaching 80% in women over 40 years of age. Most of these chromosomally abnormal embryos will either not attach to the uterus or will be miscarried early in pregnancy. This is likely the reason that women, as they age, have more difficulty conceiving and continuing a pregnancy. The risk of aneuploidy in an embryo or baby is illustrated in the chart to the left.
Why is aneuploidy more common as women get older?The cells that will eventually become eggs each have 46 chromosomes. These ‘pre-eggs’ are stored in the female ovaries from birth and women do not make more during their lifetime. After ovulation each month, one of the pre-eggs divides in half, giving one chromosome from each chromosome pair to the mature egg, for a total of 23 chromosomes. As women get older their pre-eggs get older, too, and the process of chromosome division does not work as well. Thus, as a woman ages, the mature eggs released at ovulation have a higher chance of dividing abnormally and containing extra or missing chromosomes instead of the normal number of 23. The process of abnormal division is called chromosome non-disjunction.
What is chromosome mosaicism?Chromosome mosaicism is a situation in which the cells of an embryo have different numbers of chromosomes. In some cases, a portion of the cells may have a normal number of chromosomes while another portion may be aneuploid. In other cases all the cells of the embryo may be aneuploid to different degrees.
Embryos with mosaicism may be lost in early miscarriage. Others result in perfectly healthy babies with no identifiable effects. In rare cases, an embryo with mosaicism may result in a liveborn baby with some degree of physical, mental or medical effects.
Preimplantation Genetic Screening (PGS) cannot detect mosaicism because testing is done on only one cell from the embryo and mosaicism can only be detected by testing the chromosomes of multiple individual cells. Although the actual risk is unknown, the chance to miss clinically significant mosaicism when performing PGS for aneuploidy is considered to be lower than the overall rate of mosaicism. This is because most embryos with mosaicism have been found to either contain mainly aneuploid cells, or the abnormal cell(s) ‘self-correct’ over time resulting in an embryo or fetus with normal chromosomes. Due to the fact that PGS cannot rule out mosaicism, prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis is recommended in all pregnancies achieved through PGS and IVF.
How can PGS for aneuploidy help?PGS allows the testing of each embryo separately so that those with 46 chromosomes are transferred to the mother’s uterus. Transferring those embryos with the correct number of chromosomes may increase the chance that a couple will become pregnant during a particular cycle. It may also decrease the chance for miscarriage during the pregnancy and reduce the chance for the couple to have a liveborn baby with a chromosome abnormality such as Down syndrome.
There are several technologies currently used to perform PGS for aneuploidy screening. GSN's Parental Support is the newest and most advanced technology and enables testing of all 24 chromosomes for aneuploidy with results returned in time for transfer on Day 5 with no embryo freezing required. The other commonly used technologies, both with their own benefits and limitations, are FISH and CGH.
References:
Gianaroli L, et al. 1999 Fertil Steril; 72: 837-44.
Gianaroli L. 2005 Reprod Biomed Online; 10: 633–640.
Harper JC et al. 2006 Hum Reprod; 21(1): 3-21.
Kahraman S. et al. 2000 Hum Reprod; 15 (9): 2003-7.
Kahraman S. 2004 Prenat Diagn; 24: 307–311.
Lalioti MD. 2008 Curr Opin Obstet Gynecol; 20(3): 199-204.
Mantzouratou A. 2007 Hum Reprod; 22 (7): 1844–1853.
Munne S. et al. 2003 Reprod BioMed Online 7: 91–97.
Munne S. et al. 2005 Fertil Steril 2005; 84: 331–5.
Rubio C. et al. 2005, Reprod Biomed Online; 11: 497–506.
Werlin L. et al. 2003 Fertil Steril; 80( 2) 467-468.