Mutations in Genes and Chromosomes
Genes are located on chromosomes, which are thread-like structures found within the nucleus of cells and are composed of nucleotides (adenine, thymine, guanine, and cytosine). They are the building blocks of DNA. Genes function as units of heredity when they are transferred ("inherited") from parent to offspring.
There are 23 pairs of chromosomes, one pair from each parent. Twenty-two pairs are "autosomes," and one pair are "sex chromosomes," that determine whether you are a male or a female.
A gene mutation is a permanent alteration of the sequence of DNA that makes up the gene. Mutations in genes may result from chemotherapy, radiation therapy, ionizing radiation, toxins, or they may arise spontaneously. Some can be inherited.
Mutations can change the function of genes and lead to hematologic and malignant disorders, such as leukemia, aplastic anemia, and myelodysplastic syndrome (MDS).
There are several different types of mutations that can occur. For example, a portion of a DNA segment can be deleted, inserted elsewhere, or inverted. In chromosomal rearrangements, a section of DNA is removed from one chromosome and attached to another chromosome.
The NIH (National Institute of Health) classifies gene mutations in two major ways:
Hereditary mutations are inherited from a parent and are present throughout a person's life in virtually every cell in the body. These mutations are also called germline mutations because they are present in the parent's egg or sperm cells, which are also called germ cells. When an egg and a sperm cell unite, the resulting fertilized egg cell receives DNA from both parents. If this DNA has a mutation, the child that grows from the fertilized egg will have the mutation in each of his or her cells.
Acquired (or somatic) mutations occur at some time during a person's life and are present only in certain cells, not in every cell in the body. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if an error is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed to the next generation.
Genetic changes that are described as de novo (new) mutations can be either hereditary or somatic. In some cases, the mutation occurs in a person's egg or sperm cell but is not present in any of the person's other cells. In other cases, the mutation occurs in the fertilized egg shortly after the egg and sperm cells unite. (It is often impossible to tell exactly when a de novo mutation happened.) As the fertilized egg divides, each resulting cell in the growing embryo will have the mutation. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell in the body but the parents do not, and there is no family history of the disorder.
Somatic mutations that happen in a single cell early in embryonic development can lead to a situation called mosaicism. These genetic changes are not present in a parent's egg or sperm cells, or in the fertilized egg, but happen a bit later when the embryo includes several cells. As all the cells divide during growth and development, cells that arise from the cell with the altered gene will have the mutation, while other cells will not. Depending on the mutation and how many cells are affected, mosaicism may or may not cause health problems.
Most disease-causing gene mutations are uncommon in the general population. However, other genetic changes occur more frequently. Genetic alterations that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person's health, some of these variations may influence the risk of developing certain disorders.
Testing of the Blood and Bone Marrow
There are several blood and bone marrow studies that are routinely performed in the evaluation of patients with leukemia, lymphoma, and other bone marrow disorders.
The cellularity of a bone marrow specimen is determined by looking at the marrow biopsy specimen under the microscope. Normal cellularity of a bone marrow means that 30 to70% of the marrow is composed of cells. A "hypercellular" marrow means that there are too many cells ( >70%) in the marrow (e.g., in acute leukemia).. A "hypocellular" marrow (as in bone marrow failure) means that the bone marrow is <30% cellular.
Flow Cytometry is a techniaue used to detect and measure physical and chemical characteristics of a population of cells, such as lymphocytes, from a blood or bone marrow specimen. The specimen is injected into a flow cytometer laboratory instrument, which then analyzes the characteristics of cells that pass through it.
Cytogenetics is a technique that looks for genetic mutations in chromosomes, including broken, missing, or extra chromosomes, in blood, tissue, and bone marrow specimens.
Clonality analysis looks for the presence of beta and gamma gene rearrangements that identify malignant clones of cells (e.g., lymphocytes) by analyzing their T-cell receptors (TCR) using qualitative PCR.
What is genetic testing?
Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. More than 1,000 genetic tests are currently in use, and more are being developed.
Several methods can be used for genetic testing:
◾Molecular genetic tests (or gene tests) study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder.
◾Chromosomal genetic tests analyze whole chromosomes or long lengths of DNA to see if there are large genetic changes, such as an extra copy of a chromosome, that cause a genetic condition.
◾Biochemical genetic tests study the amount or activity level of proteins; abnormalities in either can indicate changes to the DNA that result in a genetic disorder.
Examples of Genetic Mutations and Their Association with Disease
The 5q minus syndrome
In the 5q minus (5q-) syndrome, the long arm of chromosome 5 is deleted (lost). It is associated with a bone marrow disorder called myelodysplastic syndrome (MDS). MDS comprises a group of conditions in which immature blood cells fail to develop normally, resulting in too many immature cells and too few normal mature blood cells.
In 5q- syndrome, development of red blood cells is particularly affected, leading to a shortage of these cells, that results in anemia.
While many people with 5q- syndrome have little or no symptoms, some individuals develop extreme fatigue, tiredness, lightheadedness, and other symptoms, as their anemia develops and worsens.
MDS is considered a slow-growing (chronic) bone marrow cancer. In some patients, it can progress to acute myelogenous leukemia (AML).
Deletion of the long arm of chromosome 20, del(20q), is chromosomal abnormality that has been reported in approximately 10% of myeloproliferative bone marrow disorders. Approximately 4% of myelodysplastic syndromes (MDS) and 2% of acute myeloid leukemias have 20q chromosomal deletions.
It is important to note, however, that del(20q) alone is not a sufficient criterion for clinical diagnosis of a myeloid neoplasm, because it may occur with the aging process. In fact, the frequency of 20q deletions is more commonly seen in an aging population than in myeloid disorders, such as MDS. When it is seen in MDS, it may confer a relatively better prognosis. Reference: Machiella, MJ, et al. Blood Advances 2017 Feb 14; 1(6): 380–385. "Mosaic chromosome 20q deletions are more frequent in the aging population."
The Philadelphia Chromosome
The Philadelphia chromosome, which was first discovered in 1960, is an abnormally short chromosome because of a translocation (swapping) of DNA between it (chromosome 22) and chromosome 9. This results in the formation of a new fusion gene (called an "oncogene") that produces an abnormal tyrosine kinase protein called BCR-ABL. Bone marrow cells that contain the Philadelphia chromosome are often found in chronic myelogenous leukemia and sometimes found in acute lymphocytic leukemia.
Treatment with Gleevec (imatinib) is usually effective in controlling CML.
The disorder occurs when blood stem cells develop somatic mutations in the JAK2, MPL, CALR, and TET2 genes.
Long-Term Disability Claims
These are some of the tools that doctors use to diagnose and treat meyloproliferative disorders, such as leukemia, lymphoma, MDS, aplastic anemia, and others. Understanding them will help you to navigate some of the medical issues involved in a claim for long-term disability based on these conditions.