Help Me Understand Genetics

Mutations and Health

Reprinted from https://ghr.nlm.nih.gov/

Lister Hill National Center for Biomedical CommunicationsU.S. National Library of Medicine

National Institutes of HealthDepartment of Health & Human Services

Published April 17, 2018

Genetics Home Reference - https://ghr.nlm.nih.gov/Mutations and Health

Mutations and Health

Table of ContentsSection

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What is a gene mutation and how do mutations occur?

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How can gene mutations affect health and development?

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Do all gene mutations affect health and development?

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What kinds of gene mutations are possible?

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Can a change in the number of genes affect health and development?

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Can changes in the number of chromosomes affect health anddevelopment?

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Can changes in the structure of chromosomes affect health anddevelopment?

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Can changes in mitochondrial DNA affect health and development?

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What are complex or multifactorial disorders?

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What does it mean to have a genetic predisposition to a disease?

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What information about a genetic condition can statistics provide?

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How are genetic conditions and genes named?

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What is a gene mutation and how do mutations occur?A gene mutation is a permanent alteration in the DNA sequence that makesup a gene, such that the sequence differs from what is found in most people.Mutations range in size; they can affect anywhere from a single DNA buildingblock (base pair) to a large segment of a chromosome that includes multiplegenes.

Gene mutations can be classified in two major ways:

• Hereditary mutations are inherited from a parent and are presentthroughout a person’s life in virtually every cell in the body. Thesemutations are also called germline mutations because they are presentin 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 cellreceives DNA from both parents. If this DNA has a mutation, the childthat grows from the fertilized egg will have the mutation in each of hisor her cells.

• Acquired (or somatic) mutations occur at some time during a person’slife and are present only in certain cells, not in every cell in the body.These changes can be caused by environmental factors such asultraviolet radiation from the sun, or can occur if an error is made asDNA copies itself during cell division. Acquired mutations in somaticcells (cells other than sperm and egg cells) cannot be passed to thenext generation.

Genetic changes that are described as de novo (new) mutations can be eitherhereditary or somatic. In some cases, the mutation occurs in a person’s egg orsperm cell but is not present in any of the person’s other cells. In other cases, themutation 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.) Asthe fertilized egg divides, each resulting cell in the growing embryo will have themutation. De novo mutations may explain genetic disorders in which an affectedchild has a mutation in every cell in the body but the parents do not, and there isno family history of the disorder.

Somatic mutations that happen in a single cell early in embryonic developmentcan lead to a situation called mosaicism. These genetic changes are not presentin a parent’s egg or sperm cells, or in the fertilized egg, but happen a bit laterwhen the embryo includes several cells. As all the cells divide during growth anddevelopment, cells that arise from the cell with the altered gene will have themutation, while other cells will not. Depending on the mutation and how manycells are affected, mosaicism may or may not cause health problems.

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Most disease-causing gene mutations are uncommon in the general population.However, other genetic changes occur more frequently. Genetic alterationsthat occur in more than 1 percent of the population are called polymorphisms.They are common enough to be considered a normal variation in theDNA. Polymorphisms are responsible for many of the normal differencesbetween people such as eye color, hair color, and blood type. Although manypolymorphisms have no negative effects on a person’s health, some of thesevariations may influence the risk of developing certain disorders.

For more information about mutations:

The Centre for Genetics Education provides a fact sheet discussing variations inthe genetic code (http://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-2-variations-in-the-genetic-code).

More basic information about genetic mutations (https://geneed.nlm.nih.gov/topic_subtopic.php?tid=142&sid=145) is available from GeneEd.

KidsHealth from Nemours offers an introduction to genes, genetics, and geneticchanges (http://kidshealth.org/en/parents/about-genetics.html).

Additional information about genetic alterations is available from the Universityof Utah fact sheet "What is Mutation?" (http://learn.genetics.utah.edu/content/basics/mutation/)

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How can gene mutations affect health anddevelopment?

To function correctly, each cell depends on thousands of proteins to do their jobsin the right places at the right times. Sometimes, gene mutations prevent one ormore of these proteins from working properly. By changing a gene’s instructionsfor making a protein, a mutation can cause the protein to malfunction or to bemissing entirely. When a mutation alters a protein that plays a critical role inthe body, it can disrupt normal development or cause a medical condition. Acondition caused by mutations in one or more genes is called a genetic disorder.

In some cases, gene mutations are so severe that they prevent an embryofrom surviving until birth. These changes occur in genes that are essentialfor development, and often disrupt the development of an embryo in itsearliest stages. Because these mutations have very serious effects, they areincompatible with life.

It is important to note that genes themselves do not cause disease—geneticdisorders are caused by mutations that make a gene function improperly. Forexample, when people say that someone has “the cystic fibrosis gene,” theyare usually referring to a mutated version of the CFTR gene, which causes thedisease. All people, including those without cystic fibrosis, have a version of theCFTR gene.

For more information about mutations and genetic disorders:

MedlinePlus provides links to various resources about genetic disorders (https://medlineplus.gov/geneticdisorders.html).

Educational materials about genetic conditions (https://geneed.nlm.nih.gov/topic_subtopic.php?tid=142) are available from GeneEd.

The Centre for Genetics Education offers a fact sheet about genetic changes thatlead to disorders (http://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-3-gene-mutations).

The Tech Museum of Innovation offers a brief overview of genetic mutations anddisease (http://genetics.thetech.org/about-genetics/mutations-and-disease).

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Do all gene mutations affect health and development?No; only a small percentage of mutations cause genetic disorders—most haveno impact on health or development. For example, some mutations alter a gene'sDNA sequence but do not change the function of the protein made by the gene.

Often, gene mutations that could cause a genetic disorder are repaired by certainenzymes before the gene is expressed and an altered protein is produced. Eachcell has a number of pathways through which enzymes recognize and repairerrors in DNA. Because DNA can be damaged or mutated in many ways, DNArepair is an important process by which the body protects itself from disease.

A very small percentage of all mutations actually have a positive effect. Thesemutations lead to new versions of proteins that help an individual better adaptto changes in his or her environment. For example, a beneficial mutation couldresult in a protein that protects an individual and future generations from a newstrain of bacteria.

Because a person's genetic code can have a large number of mutations withno effect on health, diagnosing genetic conditions can be difficult. Sometimes,genes thought to be related to a particular genetic condition have mutations,but whether these changes are involved in development of the conditionhas not been determined; these genetic changes are known as variants ofunknown significance (VOUS) or (VUS). Sometimes, no mutations are found insuspected disease-related genes, but mutations are found in other genes whoserelationship to a particular genetic condition is unknown. It is difficult to knowwhether these variants are involved in the disease.

For more information about DNA repair and the health effects of genemutations:

The University of Utah Genetic Science Learning Center provides informationabout genetic disorders (http://learn.genetics.utah.edu/content/disorders/) thatexplains why some mutations cause disorders but others do not.

FORCE (Facing Our Risk of Cancer Empowered) explains the significanceof variants of unknown significance in cancer (http://www.facingourrisk.org/understanding-brca-and-hboc/information/hereditary-cancer/genetic-testing/basics/variants-of-uncertain-significance.php).

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What kinds of gene mutations are possible?The DNA sequence of a gene can be altered in a number of ways. Genemutations have varying effects on health, depending on where they occur andwhether they alter the function of essential proteins. The types of mutationsinclude:

Missense mutation

This type of mutation is a change in one DNA base pair (image on page9) that results in the substitution of one amino acid for another in theprotein made by a gene.

Nonsense mutation

A nonsense mutation (image on page 9) is also a change in one DNAbase pair. Instead of substituting one amino acid for another, however,the altered DNA sequence prematurely signals the cell to stop buildinga protein. This type of mutation results in a shortened protein that mayfunction improperly or not at all.

Insertion

An insertion (image on page 10) changes the number of DNA bases in agene by adding a piece of DNA. As a result, the protein made by the genemay not function properly.

Deletion

A deletion (image on page 10) changes the number of DNA bases byremoving a piece of DNA. Small deletions may remove one or a few basepairs within a gene, while larger deletions can remove an entire gene orseveral neighboring genes. The deleted DNA may alter the function of theresulting protein(s).

Duplication

A duplication (image on page 11) consists of a piece of DNA that isabnormally copied one or more times. This type of mutation may alter thefunction of the resulting protein.

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Frameshift mutation

This type of mutation occurs when the addition or loss of DNA baseschanges a gene's reading frame. A reading frame consists of groups of3 bases that each code for one amino acid. A frameshift mutation (imageon page 11) shifts the grouping of these bases and changes the codefor amino acids. The resulting protein is usually nonfunctional. Insertions,deletions, and duplications can all be frameshift mutations.

Repeat expansion

Nucleotide repeats are short DNA sequences that are repeated a numberof times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pairsequences. A repeat expansion (image on page 12) is a mutation thatincreases the number of times that the short DNA sequence is repeated.This type of mutation can cause the resulting protein to function improperly.

For more information about the types of gene mutations:

The National Human Genome Research Institute offers a Talking Glossary ofGenetic Terms (https://www.genome.gov/glossary/). This resource includesdefinitions, diagrams, and detailed audio descriptions of several of the genemutations listed above.

A brief explanation of different mutation types (http://www.yourgenome.org/facts/what-types-of-mutation-are-there) is available from yourgenome.org, a service ofthe Wellcome Trust.

The Khan Academy has a video describing the different types of gene mutations(https://www.khanacademy.org/test-prep/mcat/biomolecules/genetic-mutations/v/the-different-types-of-mutations).

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Images

In this example, the nucleotide adenine is replaced by cytosine in thegenetic code, introducing an incorrect amino acid into the protein sequence.

In this example, the nucleotide cytosine is replaced by thyminein the DNA code, signaling the cell to shorten the protein.

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In this example, one nucleotide (adenine) is added in theDNA code, changing the amino acid sequence that follows.

In this example, one nucleotide (adenine) is deleted from theDNA code, changing the amino acid sequence that follows.

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A section of DNA is accidentally duplicated when a chromosome is copied.

A frameshift mutation changes the aminoacid sequence from the site of the mutation.

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In this example, a repeated trinucleotide sequence (CAG) addsa series of the amino acid glutamine to the resulting protein.

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Can a change in the number of genes affect health anddevelopment?

People have two copies of most genes, one copy inherited from each parent. Insome cases, however, the number of copies varies—meaning that a person canbe born with one, three, or more copies of particular genes. Less commonly, oneor more genes may be entirely missing. This type of genetic difference is knownas copy number variation (CNV).

Copy number variation results from insertions, deletions, and duplications oflarge segments of DNA. These segments are big enough to include whole genes.Variation in gene copy number can influence the activity of genes and ultimatelyaffect many body functions.

Researchers were surprised to learn that copy number variation accounts for asignificant amount of genetic difference between people. More than 10 percentof human DNA appears to contain these differences in gene copy number. Whilemuch of this variation does not affect health or development, some differenceslikely influence a person’s risk of disease and response to certain drugs. Futureresearch will focus on the consequences of copy number variation in differentparts of the genome and study the contribution of these variations to many typesof disease.

For more information about copy number variation:

The Howard Hughes Medical Institute discusses the results of recent researchon copy number variation in the news release, Genetic Variation: We’re MoreDifferent Than We Thought (http://www.hhmi.org/news/genetic-variation-were-more-different-we-thought).

More information about copy number variation (https://www.dnalc.org/view/552-Copy-Number-Variants.html) is available in a video from Cold Spring HarborLaboratory.

A definition of copy number variation (https://www.genome.gov/glossary/index.cfm?id=40) is included in the Talking Genome Glossary from the NationalHuman Genome Research Institute.

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For people interested in more technical data, several institutions providedatabases of structural differences in human DNA, including copy numbervariation:

• The Centre for Applied Genomics Database of Genomic Variants(http://dgv.tcag.ca/dgv/app/home)

• The Sanger Institute: Database of Chromosomal Imbalance andPhenotype in Humans using Ensembl Resources (DECIPHER (https://decipher.sanger.ac.uk/))

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Can changes in the number of chromosomes affecthealth and development?

Human cells normally contain 23 pairs of chromosomes, for a total of 46chromosomes in each cell (image on page 17). A change in the number ofchromosomes can cause problems with growth, development, and function of thebody's systems. These changes can occur during the formation of reproductivecells (eggs and sperm), in early fetal development, or in any cell after birth. Again or loss of chromosomes from the normal 46 is called aneuploidy.

A common form of aneuploidy is trisomy, or the presence of an extrachromosome in cells. "Tri-" is Greek for "three"; people with trisomy have threecopies of a particular chromosome in cells instead of the normal two copies.Down syndrome is an example of a condition caused by trisomy (image on page18). People with Down syndrome typically have three copies of chromosome21 in each cell, for a total of 47 chromosomes per cell.

Monosomy, or the loss of one chromosome in cells, is another kind ofaneuploidy. "Mono-" is Greek for "one"; people with monosomy have one copyof a particular chromosome in cells instead of the normal two copies. Turnersyndrome is a condition caused by monosomy (image on page 19). Womenwith Turner syndrome usually have only one copy of the X chromosome in everycell, for a total of 45 chromosomes per cell.

Rarely, some cells end up with complete extra sets of chromosomes. Cells withone additional set of chromosomes, for a total of 69 chromosomes, are calledtriploid (image on page 20). Cells with two additional sets of chromosomes,for a total of 92 chromosomes, are called tetraploid. A condition in which everycell in the body has an extra set of chromosomes is not compatible with life.

In some cases, a change in the number of chromosomes occurs only in certaincells. When an individual has two or more cell populations with a differentchromosomal makeup, this situation is called chromosomal mosaicism (imageon page 21). Chromosomal mosaicism occurs from an error in cell division incells other than eggs and sperm. Most commonly, some cells end up with oneextra or missing chromosome (for a total of 45 or 47 chromosomes per cell),while other cells have the usual 46 chromosomes. Mosaic Turner syndromeis one example of chromosomal mosaicism. In females with this condition,some cells have 45 chromosomes because they are missing one copy of the Xchromosome, while other cells have the usual number of chromosomes.

Many cancer cells also have changes in their number of chromosomes. Thesechanges are not inherited; they occur in somatic cells (cells other than eggs orsperm) during the formation or progression of a cancerous tumor.

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For more information about chromosomal disorders:

A discussion of how chromosomal abnormalities happen (https://www.genome.gov/11508982#6) is provided by the National Human GenomeResearch Institute.

The Centre for Genetics Education offers a fact sheet about changes inchromosome number or size (http://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-4-chromosome-changes).

Information about chromosomal changes (http://www.eurogentest.org/index.php?id=611), including changes in the number of chromosomes, is available fromEuroGentest.

The University of Leicester's Virtual Genetics Education Center provides anexplanation of numerical chromosome aberrations (http://www2.le.ac.uk/projects/vgec/healthprof/topics/patterns-of-inheritance/chromosomal-abnormalities#numerical-aberrations).

The National Organization for Rare Disorders offers an overview of triploidy(https://rarediseases.org/rare-diseases/triploidy/).

MedlinePlus offers an encyclopedia article about chromosomal mosaicism(https://medlineplus.gov/ency/article/001317.htm).

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Images

Human cells normally contain 23 pairs of chromosomes,for a total of 46 chromosomes in each cell.

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Trisomy is the presence of an extra chromosome in cells. Downsyndrome is an example of a condition caused by trisomy.

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Monosomy is the loss of one chromosome in cells. Turnersyndrome is an example of a condition caused by monosomy.

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Cells with one additional set of chromosomes,for a total of 69 chromosomes, are called triploid.

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When an individual has two or more cell populations with a differentchromosomal makeup, this situation is called chromosomal mosaicism.

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Can changes in the structure of chromosomes affecthealth and development?

Changes that affect the structure of chromosomes can cause problems withgrowth, development, and function of the body's systems. These changes canaffect many genes along the chromosome and disrupt the proteins made fromthose genes.

Structural changes can occur during the formation of egg or sperm cells, in earlyfetal development, or in any cell after birth. Pieces of DNA can be rearrangedwithin one chromosome or transferred between two or more chromosomes. Theeffects of structural changes depend on their size and location, and whether anygenetic material is gained or lost. Some changes cause medical problems, whileothers may have no effect on a person's health.

Changes in chromosome structure include:

Translocations

A translocation occurs when a piece of one chromosome breaks off andattaches to another chromosome. This type of rearrangement is describedas balanced (image on page 25) if no genetic material is gained or lostin the cell. If there is a gain or loss of genetic material, the translocation isdescribed as unbalanced (image on page 26).

Deletions

Deletions (image on page 27) occur when a chromosome breaks andsome genetic material is lost. Deletions can be large or small, and canoccur anywhere along a chromosome.

Duplications

Duplications (image on page 28) occur when part of a chromosomeis copied (duplicated) too many times. This type of chromosomal changeresults in extra copies of genetic material from the duplicated segment.

Inversions

An inversion (image on page 29) involves the breakage of achromosome in two places; the resulting piece of DNA is reversed andre-inserted into the chromosome. Genetic material may or may not belost as a result of the chromosome breaks. An inversion that involvesthe chromosome's constriction point (centromere) is called a pericentricinversion. An inversion that occurs in the long (q) arm or short (p) arm anddoes not involve the centromere is called a paracentric inversion.

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Isochromosomes

An isochromosome (image on page 30) is a chromosome with twoidentical arms. Instead of one long (q) arm and one short (p) arm, anisochromosome has two long arms or two short arms. As a result, theseabnormal chromosomes have an extra copy of some genes and are missingcopies of other genes.

Dicentric chromosomes

Unlike normal chromosomes, which have a single constriction point(centromere), a dicentric chromosome (image on page 31) containstwo centromeres. Dicentric chromosomes result from the abnormal fusionof two chromosome pieces, each of which includes a centromere. Thesestructures are unstable and often involve a loss of some genetic material.

Ring chromosomes

Ring chromosomes (image on page 32) usually occur when achromosome breaks in two places and the ends of the chromosome armsfuse together to form a circular structure. The ring may or may not includethe chromosome's constriction point (centromere). In many cases, geneticmaterial near the ends of the chromosome is lost.

Many cancer cells also have changes in their chromosome structure. Thesechanges are not inherited; they occur in somatic cells (cells other than eggs orsperm) during the formation or progression of a cancerous tumor.

For more information about structural changes to chromosomes:

The National Human Genome Research Institute provides a list of questions andanswers about chromosome abnormalities (https://www.genome.gov/11508982),including a glossary of related terms.

Chromosome Disorder Outreach offers a fact sheet on this topic titledIntroduction to Chromosomes (https://chromodisorder.org/introduction-to-chromosomes/). This resource includes illustrated explanations of severalchromosome abnormalities.

The Centre for Genetics Education provides a fact sheet about chromosomechanges (http://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-4-chromosome-changes).

EuroGentest offers fact sheets about chromosome changes (http://www.eurogentest.org/index.php?id=611) and chromosome translocations (http://www.eurogentest.org/index.php?id=612).

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The University of Leicester's Virtual Genetics Education Center providesan explanation of structural chromosome aberrations (http://www2.le.ac.uk/projects/vgec/healthprof/topics/patterns-of-inheritance/chromosomal-abnormalities#structural-aberrations).

The Atlas of Genetics and Cytogenetics in Oncology and Haematologyprovides a technical introduction to chromosomal aberrations (http://atlasgeneticsoncology.org/Deep/Chromaber.html) and a detaileddiscussion of ring chromosomes (http://atlasgeneticsoncology.org/Deep/RingChromosID20030.html), particularly their role in cancer.

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In a balanced translocation, pieces of chromosomes arerearranged but no genetic material is gained or lost in the cell.

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An unbalanced translocation occurs when a childinherits a chromosome with extra or missing geneticmaterial from a parent with a balanced translocation.

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A deletion occurs when a chromosomebreaks and some genetic material is lost.

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A duplication occurs when part of a chromosome is copied (duplicated)abnormally, resulting in extra genetic material from the duplicated segment.

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Inversions occur when a chromosome breaks in two places and theresulting piece of DNA is reversed and re-inserted into the chromosome.Inversions that involve the centromere are called pericentric inversions;

those that do not involve the centromere are called paracentric inversions.

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An isochromosome is an abnormal chromosome with twoidentical arms, either two short (p) arms or two long (q) arms.

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Dicentric chromosomes result from the abnormal fusion of twochromosome pieces, each of which includes a centromere.

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Ring chromosomes usually occur when a chromosomebreaks in two places and the ends of the chromosome

arms fuse together to form a circular structure.

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Can changes in mitochondrial DNA affect health anddevelopment?

Mitochondria (image on page 35) are structures within cells that convertthe energy from food into a form that cells can use. Although most DNA ispackaged in chromosomes within the nucleus, mitochondria also have a smallamount of their own DNA (known as mitochondrial DNA or mtDNA). In somecases, inherited changes in mitochondrial DNA can cause problems with growth,development, and function of the body’s systems. These mutations disrupt themitochondria’s ability to generate energy efficiently for the cell.

Conditions caused by mutations in mitochondrial DNA often involve multipleorgan systems. The effects of these conditions are most pronounced in organsand tissues that require a lot of energy (such as the heart, brain, and muscles).Although the health consequences of inherited mitochondrial DNA mutationsvary widely, frequently observed features include muscle weakness and wasting,problems with movement, diabetes, kidney failure, heart disease, loss ofintellectual functions (dementia), hearing loss, and abnormalities involving theeyes and vision.

Mitochondrial DNA is also prone to somatic mutations, which are not inherited.Somatic mutations occur in the DNA of certain cells during a person’s lifetimeand typically are not passed to future generations. Because mitochondrial DNAhas a limited ability to repair itself when it is damaged, these mutations tend tobuild up over time. A buildup of somatic mutations in mitochondrial DNA hasbeen associated with some forms of cancer and an increased risk of certainage-related disorders such as heart disease, Alzheimer disease, and Parkinsondisease. Additionally, research suggests that the progressive accumulation ofthese mutations over a person’s lifetime may play a role in the normal process ofaging.

For more information about conditions caused by mitochondrial DNAmutations:

Genetics Home Reference provides background information about mitochondriaand mitochondrial DNA (https://ghr.nlm.nih.gov/primer/basics/mtdna) written inconsumer-friendly language.

An overview of mitochondrial disorders (https://www.ncbi.nlm.nih.gov/books/NBK1224/) is available from GeneReviews.

Additional information about mitochondrial disorders (https://www.cincinnatichildrens.org/service/m/mitochondrial-disorders/patients) isavailable from Cincinnati Children's Hospital Medical Center.

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The Muscular Dystrophy Association offers an introduction to mitochondrialdisorders as part of their fact sheet called Mitochondrial Myopathies (https://www.mda.org/disease/mitochondrial-myopathies).

The Neuromuscular Disease Center at Washington University providesan in-depth description of many mitochondrial conditions (http://neuromuscular.wustl.edu/mitosyn.html).

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Mitochondria provide the cell's energy.

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What are complex or multifactorial disorders?Researchers are learning that nearly all conditions and diseases have a geneticcomponent. Some disorders, such as sickle cell disease and cystic fibrosis, arecaused by mutations in a single gene. The causes of many other disorders,however, are much more complex. Common medical problems such as heartdisease, type 2 diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination withlifestyle and environmental factors. Conditions caused by many contributingfactors are called complex or multifactorial disorders.

Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk ofinheriting or passing on these disorders. Complex disorders are also difficult tostudy and treat because the specific factors that cause most of these disordershave not yet been identified. Researchers continue to look for major contributinggenes for many common complex disorders.

For more information about complex disorders:

A fact sheet about the inheritance of multifactorial disorders (http://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-11-environmental-and-genetic-interactions) is available from the Centre for GeneticsEducation.

The Children's Hospital of Wisconsin provides basic information aboutmultifactorial inheritance (http://www.chw.org/medical-care/genetics-and-genomics-program/medical-genetics/multifactorial-inheritance/) and examples ofmultifactorial disorders.

GeneEd from the National Library of Medicine and the National HumanGenome Research Institute provides a list of educational resources aboutmultifactorial inheritance and complex disease (https://geneed.nlm.nih.gov/topic_subtopic.php?tid=5&sid=8).

The National Human Genome Research Institute describes how researchersstudy complex disorders (https://www.genome.gov/10000865).

If you would like information about a specific complex disorder such as diabetesor obesity, MedlinePlus (https://medlineplus.gov/) will lead you to fact sheets andother reliable medical information. In addition, the Centers for Disease Controland Prevention provides a detailed list of diseases and conditions (https://www.cdc.gov/DiseasesConditions/) that links to additional information.

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What does it mean to have a genetic predisposition toa disease?

A genetic predisposition (sometimes also called genetic susceptibility) is anincreased likelihood of developing a particular disease based on a person'sgenetic makeup. A genetic predisposition results from specific genetic variationsthat are often inherited from a parent. These genetic changes contribute tothe development of a disease but do not directly cause it. Some people with apredisposing genetic variation will never get the disease while others will, evenwithin the same family.

Genetic variations can have large or small effects on the likelihood of developinga particular disease. For example, certain mutations in the BRCA1 or BRCA2genes greatly increase a person's risk of developing breast cancer and ovariancancer. Variations in other genes, such as BARD1 and BRIP1, also increasebreast cancer risk, but the contribution of these genetic changes to a person'soverall risk appears to be much smaller.

Current research is focused on identifying genetic changes that have a smalleffect on disease risk but are common in the general population. Although eachof these variations only slightly increases a person's risk, having changes inseveral different genes may combine to increase disease risk significantly.Changes in many genes, each with a small effect, may underlie susceptibility tomany common diseases, including cancer, obesity, diabetes, heart disease, andmental illness.

In people with a genetic predisposition, the risk of disease can depend onmultiple factors in addition to an identified genetic change. These includeother genetic factors (sometimes called modifiers) as well as lifestyle andenvironmental factors. Diseases that are caused by a combination of factorsare described as multifactorial on page 36. Although a person's genetic makeupcannot be altered, some lifestyle and environmental modifications (such ashaving more frequent disease screenings and maintaining a healthy weight) maybe able to reduce disease risk in people with a genetic predisposition.

For more information about genetic predisposition to disease:

The World Health Organization offers information about genetic predisposition toseveral common diseases (http://www.who.int/genomics/public/geneticdiseases/en/index3.html), including cancer, diabetes, cardiovascular disease, and asthma.

The Genetic Science Learning Center at the University of Utah providesmore information about calculating the risk of genetic diseases and predicting

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disease based on family history (http://learn.genetics.utah.edu/content/history/geneticrisk/).

The Coriell Personalized Medicine Collaborative explains genetic and nongeneticrisk factors (https://cpmc.coriell.org/genetic-education/genetic-and-non-genetic-risk) for complex diseases.

More detailed information about the genetics of breast and ovarian cancer(https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq), as well asother cancers (https://www.cancer.gov/publications/pdq/information-summaries/genetics), is available from the National Cancer Institute.

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What information about a genetic condition canstatistics provide?

Statistical data can provide general information about how common a conditionis, how many people have the condition, or how likely it is that a person willdevelop the condition. Statistics are not personalized, however—they offerestimates based on groups of people. By taking into account a person's familyhistory, medical history, and other factors, a genetics professional can helpinterpret what statistics mean for a particular patient.

Some statistical terms are commonly used when describing genetic conditionsand other disorders. These terms include:

Common statistical termsStatisticalterm

Description Examples

Incidence The incidence of a gene mutation ora genetic disorder is the number ofpeople who are born with the mutationor disorder in a specified group peryear. Incidence is often written in theform “1 in [a number]” or as a totalnumber of live births.

About 1 in 200,000 peoplein the United States areborn with syndrome Aeach year. An estimated15,000 infants withsyndrome B were bornlast year worldwide.

Prevalence The prevalence of a gene mutationor a genetic disorder is the totalnumber of people in a specifiedgroup at a given time who havethe mutation or disorder. This termincludes both newly diagnosed andpre-existing cases in people of anyage. Prevalence is often written inthe form “1 in [a number]” or as atotal number of people who have acondition.

Approximately 1 in100,000 people in theUnited States havesyndrome A at the presenttime. About 100,000children worldwidecurrently have syndromeB.

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Statisticalterm

Description Examples

Mortality Mortality is the number of deaths froma particular disorder occurring in aspecified group per year. Mortality isusually expressed as a total number ofdeaths.

An estimated 12,000people worldwide diedfrom syndrome C in 2015.

Lifetimerisk

Lifetime risk is the average risk ofdeveloping a particular disorder atsome point during a lifetime. Lifetimerisk is often written as a percentageor as “1 in [a number].” It is importantto remember that the risk per year orper decade is much lower than thelifetime risk. In addition, other factorsmay increase or decrease a person'srisk as compared with the average.

Approximately 1 percentof people in the UnitedStates develop disorder Dduring their lifetimes. Thelifetime risk of developingdisorder D is 1 in 100.

For more information about understanding and interpreting statistics:

NIH News in Health offers an explanation of health statistics in their article"Understanding Health Risks (https://newsinhealth.nih.gov/issue/oct2016/feature1)."

The New York Department of Health provides a basic explanation of statisticalterms (https://www.health.ny.gov/diseases/chronic/basicstat.htm), includingincidence, prevalence, morbidity, and mortality.

More detailed information about health statistics is available from Woloshin,Schwartz, and Welch's Know Your Chances: Understanding Health Statistics(https://www.ncbi.nlm.nih.gov/books/NBK115435/), which is available through theNCBI Bookshelf.

The National Cancer Institute offers additional tools for understanding cancerstatistics (https://www.cancer.gov/about-cancer/understanding/statistics).

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How are genetic conditions and genes named?Naming genetic conditions

Genetic conditions are not named in one standard way (unlike genes, whichare given an official name and symbol by a formal committee). Doctors whotreat families with a particular disorder are often the first to propose a namefor the condition. Expert working groups may later revise the name to improveits usefulness. Naming is important because it allows accurate and effectivecommunication about particular conditions, which will ultimately help researchersfind new approaches to treatment.

Disorder names are often derived from one or a combination of sources:

• The basic genetic or biochemical defect that causes the condition (forexample, alpha-1 antitrypsin deficiency);

• One or more major signs or symptoms of the disorder (for example,hypermanganesemia with dystonia, polycythemia, and cirrhosis);

• The parts of the body affected by the condition (for example,craniofacial-deafness-hand syndrome);

• The name of a physician or researcher, often the first person todescribe the disorder (for example, Marfan syndrome, which wasnamed after Dr. Antoine Bernard-Jean Marfan);

• A geographic area (for example, familial Mediterranean fever, whichoccurs mainly in populations bordering the Mediterranean Sea); or

• The name of a patient or family with the condition (for example,amyotrophic lateral sclerosis, which is also called Lou Gehrig diseaseafter the famous baseball player who had the condition).

Disorders named after a specific person or place are called eponyms. Thereis debate as to whether the possessive form (e.g., Alzheimer’s disease) or thenonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule,medical geneticists use the nonpossessive form, and this form may become thestandard for doctors in all fields of medicine.

Naming genes

The HUGO Gene Nomenclature Committee (http://www.genenames.org/)(HGNC) designates an official name and symbol (an abbreviation of the name)for each known human gene. Some official gene names include additionalinformation in parentheses, such as related genetic conditions, subtypes of acondition, or inheritance pattern. The HGNC is a non-profit organization fundedby the U.K. Medical Research Council and the U.S. National Institutes of Health.

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The Committee has named more than 13,000 of the estimated 20,000 to 25,000genes in the human genome.

During the research process, genes often acquire several alternate names andsymbols. Different researchers investigating the same gene may each give thegene a different name, which can cause confusion. The HGNC assigns a uniquename and symbol to each human gene, which allows effective organization ofgenes in large databanks, aiding the advancement of research. For specificinformation about how genes are named, refer to the HGNC's Guidelines forHuman Gene Nomenclature (http://www.genenames.org/about/guidelines).

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Lister Hill National Center for Biomedical CommunicationsU.S. National Library of MedicineNational Institutes of HealthDepartment of Health & Human Services

Published on April 17, 2018