2.1. Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy is caused by genetic changes involving the long (q) arm of chromosome 4. This condition is characterized by muscle weakness and wasting (atrophy) that worsens slowly over time. It results from changes in a region of DNA known as D4Z4, located near the end of the chromosome at a position described as 4q35. The D4Z4 region consists of 11 to more than 100 repeated segments, each of which is about 3,300 DNA base pairs (3.3 kb) long. The entire D4Z4 region is normally hypermethylated, which means that it has a large number of methyl groups (consisting of one carbon atom and three hydrogen atoms) attached to the DNA. Facioscapulohumeral muscular dystrophy results when the region is hypomethylated, with too few methyl groups attached. In facioscapulohumeral muscular dystrophy type 1 (FSHD1), hypomethylation occurs because the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats. In facioscapulohumeral muscular dystrophy type 2 (FSHD2), hypomethylation most often results from mutations in a gene called SMCHD1, which normally hypermethylates the D4Z4 region.

The segment of the D4Z4 region closest to the end of chromosome 4 contains a gene called DUX4. Hypermethylation of the D4Z4 region normally keeps the DUX4 gene turned off (silenced) in most adult cells and tissues. In people with facioscapulohumeral muscular dystrophy, hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off. Although little is known about the function of the DUX4 gene when it is turned on (active), researchers believe that it influences the activity of other genes, particularly in muscle cells. It is unknown how abnormal activity of the DUX4 gene damages or destroys these cells, leading to progressive muscle weakness and atrophy.

The DUX4 gene is located next to a regulatory region of DNA known as a pLAM sequence, which is necessary for the production of the DUX4 protein. Some copies of chromosome 4 have a functional pLAM sequence, while others do not. Copies of chromosome 4 with a functional pLAM sequence are described as 4qA or "permissive." Those without a functional pLAM sequence are described as 4qB or "non-permissive." Without a functional pLAM sequence, no DUX4 protein is made. Because there are two copies of chromosome 4 in each cell, individuals may have two "permissive" copies of chromosome 4, two "non-permissive" copies, or one of each. Facioscapulohumeral muscular dystrophy can only occur in people who have at least one "permissive" copy of chromosome 4. Whether an affected individual has a contracted D4Z4 region or a SMCHD1 gene mutation, the disease results only if a functional pLAM sequence is also present to allow DUX4 protein to be produced.

2.2. PDGFRA-associated chronic eosinophilic leukemia

PDGFRA-associated chronic eosinophilic leukemia is caused by genetic abnormalities that involve the PDGFRA gene, a gene found on chromosome 4. This condition is a type of blood cell cancer characterized by an increased number of eosinophils, a type of white blood cell involved in allergic reactions.

The PDGFRA gene abnormalities are somatic mutations, which are mutations acquired during a person's lifetime that are present only in certain cells. The most common of these abnormalities is a deletion of genetic material from chromosome 4 that removes approximately 800 DNA building blocks (nucleotides) and brings together parts of two genes, FIP1L1 and PDGFRA, creating the FIP1L1-PDGFRA fusion gene. Occasionally, through mechanisms other than deletion, genes other than FIP1L1 are fused with the PDGFRA gene. Rarely, mutations that change single DNA building blocks in the PDGFRA gene (point mutations) cause this condition.

The protein produced from the FIP1L1-PDGFRA fusion gene (as well as other PDGFRA fusion genes) has the function of the PDGFRA protein, which stimulates signaling pathways inside the cell that control many important cellular processes, such as cell growth and division (proliferation) and cell survival. Unlike the normal PDGFRA protein, however, the fusion protein is constantly turned on (constitutively activated), which means the cells are always receiving signals to proliferate. Similarly, point mutations in the PDGFRA gene can result in a constitutively activated PDGFRA protein. When the FIP1L1-PDGFRA fusion gene or point mutations in the PDGFRA gene occur in blood cell precursors, the growth of eosinophils (and occasionally other blood cells) is poorly controlled, leading to PDGFRA-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

2.3. Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4 at a position described as 4p16.3. The signs and symptoms of this condition are related to the loss of multiple genes from this part of the chromosome. The size of the deletion varies among affected individuals; studies suggest that larger deletions tend to result in more severe intellectual disability and physical abnormalities than smaller deletions.

The region of chromosome 4 that is deleted most often in people with Wolf-Hirschhorn syndrome is known as Wolf-Hirschhorn syndrome critical region 2 (WHSCR-2). This region contains several genes, some of which are known to play important roles in early development. A loss of these genes leads to developmental delay, a distinctive facial appearance, and other characteristic features of the condition. Scientists are working to identify additional genes at the end of the short arm of chromosome 4 that contribute to the characteristic features of Wolf-Hirschhorn syndrome.

2.4. Other chromosomal conditions

Some deletions of genetic material from the short (p) arm of chromosome 4 do not involve the critical region WHSCR-2. These deletions cause signs and symptoms that are distinct from those of Wolf-Hirschhorn syndrome, including mild intellectual disability and, in some cases, rapid (accelerated) growth. People with this type of deletion usually do not have seizures.

Trisomy 4 occurs when cells have three copies of chromosome 4 instead of the usual two copies. Full trisomy 4, which occurs when all of the body's cells contain an extra copy of chromosome 4, is not compatible with life. A similar but somewhat less severe condition called mosaic trisomy 4 occurs when only some of the body's cells have an extra copy of chromosome 4. The signs and symptoms of mosaic trisomy 4 vary widely and can include heart defects, abnormalities of the fingers and toes, and other birth defects. Mosaic trisomy 4 is very rare; only a few cases have been reported.

Other changes in the number or structure of chromosome 4 can have a variety of effects including delayed growth and development, intellectual disability, distinctive facial features, heart defects, and other medical problems. Changes involving chromosome 4 include an extra piece of the chromosome in each cell (partial trisomy 4), a missing segment of the chromosome in each cell (partial monosomy 4), and a circular structure called a ring chromosome 4. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

2.5. Cancers

Changes in chromosome 4 have been identified in several types of human cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. For example, rearrangements (translocations) of genetic material between chromosome 4 and several other chromosomes have been associated with leukemias, which are cancers of blood-forming cells.

A specific translocation involving chromosome 4 and chromosome 14 is commonly found in multiple myeloma, which is a cancer that starts in cells of the bone marrow. The translocation, which is written as t(4;14)(p16;q32), abnormally fuses the WHSC1 gene on chromosome 4 with part of another gene on chromosome 14. The fusion of these genes overactivates WHSC1, which appears to promote the uncontrolled growth and division of cancer cells.