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Aneuploidy

What Is It, Causes, Diagnosis, and More

Author: Anna Hernández, MD

Editors: Alyssa Haag, Ian Mannarino, MD, MBA, Kelsey LaFayette, DNP, ARNP, FNP-C

Illustrator: Jessica Reynolds, MS

Copyeditor: Stacy Johnson, LMSW

What is aneuploidy?

Aneuploidy is a chromosomal anomaly in which a cell has an extra or missing chromosome. Chromosomes are thread-like structures found in the nucleus of cells and contain long strands of DNA, which is the molecule that carries the genetic information necessary for the development and functioning of an organism. Human somatic cells (i.e., all cells besides the gametes [egg and sperm]) carry 46 chromosomes: two copies of the 22 autosomal (i.e. non-sex) chromosomes and two sex chromosomes, either X or Y. In genetically female individuals, there are two X chromosomes (46XX), while in genetically male individuals, there is an X and a Y chromosome (46XY). 

Aneuploidy happens when an individual has an extra chromosome in a cell, resulting in 45 chromosomes. When one member is missing, it is called monosomy, whereas if there is an extra chromosome that joins a pair, trisomy. In rare cases, an individual may have more than one additional chromosome. Tetrasomy and pentasomy refer to the presence of four or five copies of a chromosome.

The most common aneuploidies in humans are trisomies, and of those, the only ones that are compatible with life are trisomy 21 (Down syndrome), trisomy 13 (Edwards syndrome), and trisomy 18 (Patau syndrome). Sex chromosomes can also be affected with trisomy and monosomy, resulting in genetic disorders like Turner syndrome, which is characterized by having 45 chromosomes with only one X chromosome, and Klinefelter syndrome, where genetically male individuals have an extra copy of the X chromosome. Although rarely seen in humans, sex chromosome tetrasomy and pentasomy have been reported.

What causes aneuploidy?

Most aneuploidies occur due to nondisjunction when chromosomes do not separate properly during cell division. When germ cells divide to create sperm and egg during meiosis, the genetic information carried on chromosomes is equally divided into two daughter cells. Meiosis has two stages: meiosis I, where a diploid cell with 46 chromosomes is divided into two daughter cells with 23 chromosomes, and meiosis II, where each of the daughter cells in meiosis I get split into two, resulting in a total of four haploid cells with 23 chromosomes each.

Nondisjunction typically occurs during meiosis I, where one of the chromosome pairs in the egg or sperm cell does not split, resulting in two cells with an extra chromosome and two cells with a missing chromosome. Nondisjunction can also occur in meiosis II, where a sister chromatid does not separate, resulting in one cell with an extra chromosome, one cell missing a chromosome, and two cells with the correct number of chromosomes. If a sperm cell or egg combines with one of the cells with an extra chromosome, then the combined cell, or zygote, will have three chromosomes instead of two, resulting in trisomy. On the other hand, if they combine with a cell missing a chromosome, the zygote will only have one chromosome, resulting in monosomy. 

Because most cases of aneuploidy arise from nondisjunction errors in maternal meiosis, advanced maternal age is a significant risk factor for trisomy. For mothers younger than 20 years old, trisomy 21 occurs in about 1 out of 1500 births. For mothers younger than 45 years old, it can happen in about 1 in 25 births. 

Apart from nondisjunction, Robertsonian translocation accounts for a small percentage of all cases of aneuploidy. Each chromosome is divided into two sections, or arms, based on the location of a narrowing called the centromere. Robertsonian translocation only affects acrocentric chromosomes, which have a centromere at the very end of the chromosome. When two acrocentric chromosomes break at their centromeres, the two long arms may fuse, resulting in a single chromosome with both long arms; and the two short arms may fuse to form a smaller chromosome with both short arms.  The chromosome with short arms typically carries nonessential genes and may be lost by the end of meiosis with no clinical implications. On the other hand, the chromosome with both long arms contains the majority of genetic material on the original chromosome. Since the long arms carry most of the genetic material, cells with the long arm chromosome will essentially have an extra chromosome, which, combined with the other gamete, will result in trisomy. Cells with short arms nearly miss a chromosome and may result in monosomy combined with a normal gamete.

Finally, aneuploidies may not necessarily be present in all cells in an individual. When aneuploidy is detected in a fraction of cells in an individual, it is called mosaicism. This can occur when a cell in a developing fetus experiences a nondisjunction during mitosis, resulting in aneuploidy in the culprit cell and its lineage. Individuals who are mosaic for chromosomal aneuploidy tend to have less severe symptoms when compared to individuals who have complete aneuploidy. 

What are the signs and symptoms of aneuploidy?

Signs and symptoms of aneuploidy depend on the type of aneuploidy. Most aneuploidies affecting autosomal chromosomes are incompatible with life and often result in spontaneous abortions in the first few weeks of pregnancy. There are only three viable autosomal aneuploidies, and they include trisomy 21 (Down syndrome), trisomy 13 (Edwards syndrome), and trisomy 18 (Patau syndrome). Most aneuploidies affecting autosomal chromosomes are incompatible with life and often result in spontaneous abortions in the first few weeks of pregnancy. 

Down syndrome is the most common chromosomal disorder in live births, affecting about 1 in every 700 infants. Common signs and symptoms include a simian crease in the hands, a gap between the first two toes, a flat facial profile, and epicanthal folds. Individuals with Down syndrome may also have intellectual disability, cardiovascular complications, neck instability (i.e., atlantoaxial instability), and gastrointestinal malformations, as well as an increased risk of leukemia and Alzheimer disease.

Edwards syndrome is the second most common chromosomal disorder in live births, affecting about one in every 8,000 infants. Most fetuses with Edwards syndrome die before birth, and those that survive pregnancy die within a few weeks to months after birth due to complications. Infants that survive typically have dysmorphic features, like a small head; small eyes; low-set ears; cleft lip and palate; and rocker bottom feet, which is when the soles of the feet are rounded and smooth like the bottom of a rocking chair. They also typically develop a severe intellectual disability, failure to thrive, and complications related to heart, kidney, and gastrointestinal malformations. 

Finally, the third most common autosomal trisomy is Patau syndrome, which affects about 1 in 15,000 infants. The most classic characteristics of Patau syndrome are severe intellectual disability, skull and nose deformities; polydactyly; and cutis aplasia (i.e., scalp lesions with the absence of skin). More severe defects include cyclopia or having a single eye at the center of the forehead. Like those with Edwards syndrome, fetuses with Patau syndrome often die due to complications before birth or shortly after. 

Aneuploidies affecting sex chromosomes tend to be less severe due to the smaller genetic contribution of chromosomes X and Y to overall human development. The most common sex chromosome disorders are Klinefelter syndrome and Turner syndrome. Klinefelter syndrome occurs when an individual with an XY genotype inherits one or more additional X chromosomes. Common features of Klinefelter syndrome include male sterility; small external genitals; a characteristic physical appearance, including long legs, short torso, scarce facial and body hair, and gynecomastia (i.e., development of breast tissue). On the other hand, Turner syndrome occurs when one X chromosome is either completely or partially absent. Signs and symptoms of Turner syndrome include non-functional, fibrous ovaries; short stature; lymphedema; neck webbing; and congenital heart and renal defects. 

How is aneuploidy diagnosed?

Diagnosis of aneuploidy is achieved through a karyotype analysis, which is the process of pairing and ordering all the individual’s chromosomes to detect abnormalities. Karyotyping can be done prenatally to detect aneuploidy before birth via chorionic-villus sampling between 9 and 11 weeks gestation or amniocentesis between 15 and 20 weeks gestation. Because chorionic-villus sampling and amniocentesis are invasive procedures, they are only conducted in individuals with a risk of aneuploidy when assessed through non-invasive prenatal testing. 

Prenatal screening tests include the combined test during the first trimester of pregnancy, which consists of a nuchal translucency scan and measuring PAPP-A and beta-hCG serum hormone levels. Screening during the second trimester typically consists of a quadruple test, which measures serum levels of alpha-fetoprotein (AFP) serum levels, unconjugated estriol (uE3), beta-hCG, and inhibin A. An alternative to these classic screening tests is the assessment of cell-free DNA in a maternal blood sample, which analyzes the presence of fetal DNA in maternal blood and can be done as early as ten weeks gestation.

How is aneuploidy treated?

Despite years of intense research, no targeted therapies are available to cure aneuploidy. Ultimately, the management of aneuploidy depends on the specific needs and complications.

For individuals with Down syndrome, improved medical care has led to much greater longevity and quality of life, allowing individuals to thrive and develop. Management of Down syndrome may involve early intervention programs, including speech, physical, occupational, and educational therapy and treatment of related health problems. On the other hand, management of other trisomies like Edwards and Patau syndrome is only supportive and focuses on treating life-threatening complications, such as congenital malformations and infections. Unlike those with autosomal aneuploidies, most individuals with sex aneuploidies have an average lifespan, and many symptoms can be treated with hormone supplementation. 

What are the essential facts to know about aneuploidy?

Aneuploidy is the presence of an abnormal number of chromosomes in a cell. Having an extra or missing chromosome affects almost every body system and is a common cause of genetic disorders, including Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), or Patau syndrome (trisomy 13). The risk of aneuploidy during pregnancy is higher in individuals with advanced maternal age and can be assessed through several non-invasive prenatal tests. Definitive diagnosis is achieved through an invasive procedure like chorionic villus sampling or amniocentesis with subsequent fetal karyotyping. Unfortunately, because aneuploidies are due to chromosomal abnormalities, there is no known cure, and management is mainly supportive and focuses on treating life-threatening complications.

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