4.2 Genetics

Abnormal Chromosome Number

All body cells contain the diploid number (2N) of chromosomes, 46. The sex cells (egg and sperm), on the other hand, contain only the haploid number (N), or 23 chromosomes. Sometimes, a replication error occurs, and a cell contains an abnormal number of chromosomes. There are two types of numerical chromosomal abnormalities: aneuploidy, which is an abnormal number of chromosomes, and polyploidy, which is an abnormal number of chromosome sets (Milani & Tadi, 2023). Aneuploidies can take the form of a monosomy, which is when a cell is missing a chromosome, or the more common trisomy, which is when the cell has an extra chromosome. An example of polyploidy is triploid cells (3N), which have 3 full sets of chromosomes, or 69 chromosomes.

These chromosomal numerical errors most commonly occur as a result of faulty mitotic or meiotic divisions of the egg or sperm, but they can also occur during embryonic development or through parental inheritance (Milani & Tadi, 2023).

During meiosis, the paired chromosomes normally separate, allowing one complete set of chromosomes to be found in each daughter cell. However, if this separation process doesn’t happen correctly, an extra chromosome or set of chromosomes can be found in one daughter cell, with the other daughter cell missing chromosomes (Figure 4.8). This is known as nondisjunction. Nondisjunction is more common in older persons assigned female at birth and in patients exposed to certain environmental toxins (Wasielak-Politowska & Kordowitzki, 2022).

Figure 4.8 Nondisjunction in Sperm Cells Abnormal chromosomal numbers occur because of nondisjunction, the improper division of chromosomes during meiosis or mitosis. In sperm cells, nondisjunction can occur at either meiosis I or meiosis II. (credit: modification of work from Concepts of Biology. attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Many aneuploidies are incompatible with life, but a few relatively common conditions are caused by either trisomies or monosomies. See 10.4 Fetal Growth and Development for more information about common aneuploidies. If patients desire genetic testing, screening can be done starting in the first trimester.

Abnormal Chromosome Structure

Structural chromosomal abnormalities occur when there are changes to the chromosome’s structure, such as missing or extra genetic material. These changes can be balanced (there are changes to the arrangement of the genes, but there is no loss or gain of genetic material) or unbalanced (there is a loss or gain of genetic material). People with balanced mutations are less likely to have a phenotypic effect, though it is possible, because they retain all the genetic material (Yahaya et al., 2021).

Like numerical abnormalities, structural chromosomal abnormalities also occur because of errors in cell division, parental inheritance, or early embryonic division (National Human Genome Research Institute, 2020). Many different types of mutations can cause these types of errors to occur (Yahaya et al., 2021):

• Deletion: A piece of the chromosome is missing.
• Duplication: A piece of the chromosome is repeated, causing additional genetic material.
• Inversion: One piece of the chromosome is taken out and turned upside down before reconnecting with the chromosome.
• Translocation: A piece of the chromosome is moved to a different location on the same chromosome or to a different chromosome.
  • Reciprocal translocation: Pieces from two chromosomes are exchanged.
  • Robertsonian translocation: The short arm of two chromosomes breaks off, allowing the two long arms to stick together in one long chromosome.

These mutations can occur in any chromosome or group of chromosomes and can cause a wide variety of effects, ranging from phenotypically normal to incompatible with life. Even very small unbalanced mutations can have significant effects on the person.

Abnormal Sex Chromosomes

The sex chromosomes, X and Y, can also be affected by both numerical and structural chromosomal abnormalities. These conditions are more likely to cause reproductive problems and infertility (Wang et al., 2022). The most common sex chromosome abnormalities are presented in Table 4.2.

Autosomal Dominant Inheritance

An autosomal dominant inheritance disorder is caused when only one copy of the dominant allele is needed to express the trait. Because only one gene is needed to express the trait, there is a 50 percent chance of inheritance from an affected, heterozygous parent (Figure 4.9). These types of disorders tend to run in families across multiple generations, known as vertical transmission. The severity of the disorder can sometimes range significantly, even between one generation and the next. It is also possible for these diseases to form because of a new mutation that has not been inherited from the previous generation. Patients who have a family member with an autosomal dominant disease may request genetic testing to see if they are a carrier, particularly if the disorder does not cause symptoms until later in life, as in Huntington disease. In some cases, the result can affect childbearing decisions or other major life choices (Severijns et al., 2021).

Figure 4.9 Autosomal Dominant Inheritance This diagram demonstrates the inheritance of autosomal dominant traits. Note how 50 percent of the children of a parent with the gene will also inherit the genetic trait or disorder. (attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Autosomal Recessive Inheritance

Genes that are autosomal recessive require the presence of both recessive alleles for the trait to be expressed. Someone who is affected by these types of disorders must have inherited the recessive gene from both parents (National Human Genome Research Institute, 2023). Heterozygous individuals, those who carry both the dominant and recessive alleles, have a 50 percent chance of passing the recessive allele to their children. If both parents carry the gene, their child has a 25 percent chance of contracting the disease (Figure 4.10). Offering carrier testing to couples trying to conceive may help to identify and reduce the risk of these diseases. Autosomal recessive diseases have a horizontal pattern of inheritance, meaning that they are found among siblings, but not people of earlier generations. They are found equally in males and females but may be found more frequently in particular ethnicities or populations.

Figure 4.10 Autosomal Recessive Inheritance In the autosomal recessive pattern of inheritance, when two carriers have children, each child has a 25 percent chance of having the disease and a 50 percent chance of being carrier. (attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Some of the more common diseases that follow the autosomal patterns of inheritance are presented in Table 4.3.

X-Linked Recessive Inheritance

X-linked genes are carried on the X chromosome. When these diseases are passed down to the next generation, this is referred to as X-linked inheritance. These diseases disproportionately affect more males than females because males must inherit only one affected X chromosome to be affected. Females must inherit two copies, one from each parent, to have the disease.

Female carriers have a 50 percent chance of passing the affected X chromosome to their children. Affected males will pass the carrier gene on to any female children. Those female children will be carriers if they receive a normal X chromosome from their female parent, but they will have the disease if they inherit an affected X chromosome instead (Figure 4.11). Examples of X-linked recessive disorders include hemophilia and color-blindness.

Figure 4.11 X-Linked Inheritance The genes for some diseases are carried on the X chromosome. Male offspring have a 50 percent chance of inheriting the disorder from a carrier mother. (attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Fragile X syndrome is another X-linked recessive disease with a complicated inheritance pattern. It occurs during replication of the X chromosome where specific proteins are skipped instead of replicated. This pattern can occur only a few times (5 to 44 skipped), causing fewer complications, or many times (>200 skipped), causing the full condition (The National Fragile X Foundation, n.d.). Complications of fragile X include intellectual disability, behavior problems, and physical differences, such as large, protruding ears, prominent forehead, and hypermobile joints (The National Fragile X Foundation, n.d.).

Preimplantation Genetic Screening/Diagnosis (PGS/D)

Preimplantation genetic screening/diagnosis (PGS/D) is a form of very early prenatal screening that can occur only in conjunction with in vitro fertilization (IVF). During this procedure, a single cell is removed for biopsy from an embryo that was formed in the lab (University of California San Francisco, n.d.).

• PGS occurs when the embryo is screened for chromosomal aneuploidies, such as Down syndrome.
• PGD occurs when the embryo is analyzed for the presence of a particular gene, such as the gene associated with cystic fibrosis. This testing is particularly helpful in couples who have had carrier screening that identifies both partners as carrying a particular genetic disorder.

Healthy embryos can then be selected for later embryo transfer.

Prenatal Screening

The series of tests that are performed during pregnancy to determine the risk of the fetus having an aneuploidy, a neural tube defect, or another abnormality suggestive of a genetic disorder is called the prenatal screening. The tests include the following:

• First Trimester Screening: Performed between 10 and 13 weeks of pregnancy, the first trimester screen consists of a blood test and ultrasound. The blood test looks at two substances: pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotropin (hCG). Abnormal levels of either of these could indicate a chromosomal abnormality. The ultrasound, called a fetal nuchal translucency test, looks at the back of the fetus’s neck. Increased thickening or fluid is an abnormal result and could indicate a chromosomal abnormality.
• Second Trimester Screening: The second trimester screening consists of a blood test between 15 and 22 weeks of pregnancy measuring alpha-fetoprotein, hCG, unconjugated estriol, and inhibin A. An ultrasound can also be performed between 18 and 22 weeks of pregnancy. The blood test looks for markers that suggest Down syndrome, Edwards syndrome, and neural tube defects. The ultrasound is a comprehensive test that measures the fetus’s abdominal organs, limbs, brain, spine, and facial features for signs of a chromosomal abnormality.
• Noninvasive Prenatal Testing (NIPT): NIPT is a maternal blood test that is offered early in the first trimester. The test looks at small fragments of fetal DNA that are found in the pregnant person’s bloodstream. Those cells are from the placenta and are shed throughout the pregnancy. While this type of test does not definitively diagnose a genetic disorder, it does screen for chromosomal abnormalities, like trisomies and aneuploidy (Goldwaser & Klugman, 2018).

Prenatal Diagnosis

Prenatal diagnostic testing is more specific than screening. Patients with positive results on their screening test or those who are at higher risk for having a fetus with a genetic disorder (such as older patients) are good candidates for this type of testing. Samples are taken directly from the fetal tissues and used for chromosomal analysis. Table 4.4 compares the two main types of procedures used for prenatal diagnosis: chorionic villus sampling, which analyzes placental cells, and amniocentesis, which evaluates the amniotic fluid surrounding the fetus.