Developmental history of medical genetics Basic aspects of chromosome structure and the important processes of meiosis and mitosis have been presented in Chapter

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Medical Genetics

Medical Genetics ?

It is a synthetic subject which can research the human hereditary diseases and human pathogenetic genetics by genetic theories and methods.

It can study the problems of pathogenetic mechanism,transmitted types, epidemiology, diagnosis, therapy, prognosis and prevention of genetic diseases for controlling the occurrence and popular of genetic diseases in the population, and offer the methods and measures for diagnosis, therapy and prevention of genetic diseases to improve human health and boost population diathesis.

Therefore, Medical Geneticsis a momentous course of preclinical medicine and a bridge course between the preclinical and clinical medicine.

1.Developmental history of medical genetics

Genetics had its roots in the 19th century when, in 1865, Gregor Mendel, a monk and then abbot(superintendent of male monastery) in an Augustinian monastery, discovered the laws of inheritance in garden peas, a feat that was overlooked until “Mendelism” was rediscovered in 1900. Walther Flemming first visualized human chromosomes in tumor cells in 1882, and Waldeyer introduced the term “chromosome” in 1888.During the 1880s, Roux, deVries,and Eismann developed the theory that chromosomes carry determinants(determinative factor )of heredity and development, and in 1903, Walter Sutton and Theodor Boveri proposed the chromosomal theory of Mendelism. In  this same decade, the concept of “inborn errors of metabolism” was introduced by Archibald Garrod, which he formally proposed in his Croonian lectures, published in 1909, discussing alkaptonuria, pentosuria, cystinuria, and albinism. During the next half century, genetics developed as a basic science, with a focus on Drosophila, the mouse, and corn as experimental systems.

Most human studies were based on biostatistics and population-based mathematical analyses. However, during this time, Mendelian inheritance was defined in a number of disorders, such as albinism, brachydactyly, and symphalangism. During this era, the concept of “eugenics” evolved, resulting in a societal attempt to improve the gene pool and prevent dissemination of bad genes into future generations. This led to a variety of eugenic practices throughout the world, where individuals with mental deficiency as well as those with physical malformations were prohibited from reproducing, with programs of forced sterilization, etc. The eugenic movement culminated in the “justification” of the Nazi holocaust, but after the Second World War, eugenics and its base in human genetics fell into disrepute.

A scientific approach to human genetics emerged in 1948 with the establishment of the American Society of Human Genetics(ASHG), but it must be stated that the majority of its founding board of directors were members of the American Eugenics Society. Few medical doctors were involved in human genetics at that time, the majority being PhDs with backgrounds in formal (population or statistical genetics), Drosophila, or mouse genetics. Many of these PhD geneticists began studying the inheritance of single gene disorders in human, and some became excellent clinicians in the description of syndromes and birth defects. These included such individuals as Curt Stern in Berkeley, Norma Ford Walker in Toronto, and F. Clarke Fraser in Montreal (who gained an MD after his earlier PhD but never took an internship. Annual meetings of the ASHG began in 1948, and the first  International Congress of Human Genetics was held in Gepenhagen in 1956, with regular congresses occurring every 5 y since then. One of the first MDs to become a human geneticist was James Neel, whose studies ranged from hemoglobinopathies to complex disorders, such as diabetes and mathematical genetics in diverse populations. Neel was an internist, as were most of the other major medical figures in genetics in 1950s, including Victor McKusick at Johns Hopkins, Arno Motulsky in Seattle, and Alex Bearn and Kurt Hirschhorn in New York. There were few formally trained pediatricians in medical genetics in the 1950s, an outstanding exception being Barton Childs at Johns Hopkins. These adult-trained medical geneticists each developed training programs in genetics, with most of their early trainees being internists as well. However, with the explosive developments in the genetics of childhood diseases in the 1960s and 1970s, many pediatricians sought training in genetics, and training programs in medical genetics flourished in departments of pediatrics. Indeed, many of the second-generation internal medicine-trained geneticists joined departments of pediatrics, and they themselves trained numerous pediatricians over the years. Many of the early medical geneticists based in pediatric departments were originally trained as internists, including David Nathan, Charles Epstein, John Littlefield, Judith Hall, Ian Porter, and David Rimoin. Simultaneously, a number of pediatric-trained medical geneticists emerged, such as Charles Scriver, William Nyhan, Rodney Howell, John Opitz, Henry Nadler, Jurgen Spranger, Barbara Migeon, Jim Sidbury, Michael Kaback, and Murray Feingold. A  number of highly productive genetics units were established in children’s hospitalsand pediatric departments throughout Europe. One of the first was established at the Royal Children’s Hospital (Great Ormond Street) in London under the direction of J. Fraser Roberts, followed by Cedric Carter, Marcus Pembry, and Robin Winter. Paul Polani at Guys Hospital in London made major contributions to the field. Maurice Lamy developed an important genetics center at the Hospital des EnfantsMalades in Paris, with the help of such luminaries as Maroteaux, Frezal, and de Grouchy. Clinical genetics flourished in Kiel, Germany, with H.RWiedemann and his student Jurgen Spranger, who subsequently developed a genetics center in the department of pediatrics in Mainz.

2. Disciplines within Medical Genetics


Biochemical genetics:

Molecular genetics


Genetic epidemiology:


Cancer genetics:

Morbid genetics:

Molecular diagnostics:

Eugenics, etc.

2.1  Cytogenetics

The beginning of modern human cytogenetics was made possible by the development of tissue culture, the ability to use peripheral blood after immunogenetic stimuli of lymphocytic mitosis, use of mitosis-arresting agents, hypotonic dividing cells, and a variety of staining techniques. Aside from the discovery in 1956 of the correct human chromosome number of 46, most of the descriptions of chromosome abnormalities came from departments of pediatrics in their study of abnormal children. The first of these was the finding by Lejeune of an extra chromosome 21 in Down syndrome in 1959. This was quickly followed by the discovery of sex chromosome abnormalities including 45 Xin Turner syndrome, 47XXY in Klinefelter, and other numerical abnormalities of  sex chromosomes. Not long thereafter, other autosomal trisomies were discovered, primarily class of chromosome aberrations found early in cytogenetics was a variety of patients who had mosaicism and had two or more chromosomally different cell lines in their bodies. The most important of these were XY/XO in male pseudo-hermaphroditism and XX/XO in X-chromatin positive Turner syndrome patients. A major class of abnormalities discovered through the study of children with congenital abnormalities was changes in the structure of chromosomes. These include isochromosomes in the case of the long arm of the X associated with Turner syndrome, deletions, including those of the short arm chromosome 5 in the Cat cry syndrome, and the short arm of chromosome 4 in the Wolf-Hirschhorn syndrome, as well as balanced and unbalanced translocations, the latter resulting in partial duplications and deficiencies of  parts of chromosomes. One of the early forms of the latter resulted in extra material from chromosome 21, translocated often to chromosome 14 in cases of familial Down syndrome .

In 1969 and 1971, methods of chromosome banding led to far more accurate descriptions of chromosomal abnormalities, particularly those involving structural changes. This led to the concept of contiguous gene deletion syndromes by Roy Schmickel. Although fluorescent banding techniques were used extensively in the early 1970s, to this day, G-banding is the most common method of studying chromosomes from blood and other tissue.

It was soon found that virtually all malignant cells carried various chromosomal abnormalities, a finding predicted in 1914 by Boveri. The first of these was the Philadelphia chromosome, diagnostic of chronic myelogenous leukemia by Nowell and Hungerford. Janet Rowley later discovered this to be due to a translocation between the long arms of chromosomes 9 and 22, leading to uncontrolled activation of a gene partly responsible for cell division, thereby leading to uncontrolled growth of myeloid cells. Careful study found many similar instances of balanced and unbalanced translocations in leukemia and lymphoma involving various chromosomes and various cell growth genes. These have become indispensable tools in the accurate diagnosis and tailoring of therapy in various oncologic disorders, especially in the childhood leukemias and lymphomas. High-resolution banding in prophase was developed in 1977 by Francke Yunis, and the Manilovs, which improved delineationof microdeletions in solid tumors, such as Wilms and retinoblastoma.

In the past few years, new technology has led to even more refined diagnosis of chromosomal imbalances. These have included the use of fluorescent probes (fluorescence in situ hybridization) for the purpose of accurate identification of chromosomes and their parts, as well as the mapping of genes to specific sites on chromosomes. These have revealed specific chromosomal abnormalities in diseases such as Langer-Giedion, Prader-Willi, DiGeorge, and Beckwith-Wiedemann syndromes. Variations of this method have led to detection of small duplications and deletions by comparative genomic hybridization (CGH), both in individuals and to an even more important extent in cancer cells. In addition, techniques have been developed for multicolor identification of chromosomes so that a single fluorescent study can identify multiple abnormalities, including those involving translocations, in a single cell, particularly important in complex chromosomal abnormalities in malignant cells. Recently, even greater refinement and accuracy have been achieved by hybridization of DNA or RNA to microarrays, leading to discovery of over- and underexpression of specific genes in malignant cells. Major advances in the understanding of the pathogenesis of Down syndrome has  been accomplished in departments of pediatrics by Charles Epstein, David Cox, and Julie Korenberg and in understanding chromosomal imprinting by Arthur Beaudet and Judith Hall. One of the most important applications of all of these cytogenetic techniques has been in the prenatal diagnosis of chromosomally abnormal fetuses, allowing families the options of terminating such pregnancies and allowing them to pursue pregnancies with chromosomal normality. Cecil Jacobsen in DC, Neal McIntyre in Cleveland, and Henry Nadler in Chicago were pioneers in this area.1.4.

2.2 Biochemical genetics

The field of biochemical  genetics dates back to Garrod, who in the  early part f the 20th century coined the term “inborn errors of metabolism.” The field has grown to such a degree that the eighth edition of The Metabolic and Molecular Basis of Inherited Diseases now fills four large volumes. The great majority of these disorders are prevalent in the pediatric population, and often they cause problems in the newborn or the infant. Many of them are responsible for mental retardation and, to a greater or lesser degree, physical abnormalities.

The first inborn errors to have their enzyme deficiency discovered were glucose-6-phosphatase deficiency in glycogen storage disease type I and phenylalanine hydroxylase in phenylketonuria(PKU) followed by the description of lysosomal enzyme disorders in the 1960s. The development of new electrophoretic and chromatographic methods in protein and enzyme biochemistry led to the rapid elucidation of many enzyme deficiencies in amino acid and organic acid  metabolism in the 1960s and 1970s. Because these disorders affected primarily children and there was rapid development of methods for the treatment and prevention of the associated mental retardation, departments of pediatrics became the natural site for their  study and care. This resulted in the training of numerous pediatricians in biochemical genetics and the establishment of divisions of medical genetics within departments of pediatrics. Major advances were made in the study of inborn errors in pediatric centers in Baltimore, Boston, New Haven, Chicago, Denver, Montreal, San Diego, Los Angeles, and Philadelphia. The early investigators in biochemical genetics, such as Barton Childs, Harry Harris, Rodney Howell, Charles Scriver, and Leon  Rosenberg, trained numerous young physician scientists, who became experts in inborn errors of metabolism and built active units in pediatrics departments throughout the United States.

In addition to the inborn errors of amino acid and organic acid metabolism, numerous other metabolic fields evolved in the 1970s and 1980s, with the description of lysosomal enzyme disorders (e.g. mucopolysaccharidoses), peroxisomal enzyme defects (e.g. Zellweger syndrome), urea cycle defects (e.g. citrullinemia), carbohydrate metabolic disorders (e.g. glycogen storage diseases and galactosemia), purine and pyrimidine defects (e.g. Lesch-Nyhan syndrome), and disorders of mineral metabolism (e.g. Wilson’s disease and hemachromatosis). The development of cell culture techniques and somatic cell genetics, including the development of selective media, such as HAT (hypoxanthine-aminopterin-thymidine) by John Little-field, and the concept of complementation, paved the way in the 1960s for many of these biochemical discoveries, such as the definition of the enzyme defect in HPRT (hypoxanthine guanine phosphoribosyl transferase) Lesch-Nyhan syndrome and the enzyme defects in the mucopoly-saccharidoses. The 1970s and 1980s witnessed the description of numerous enzymaticdefects in diseases involving carbohydrate, protein, and lipid metabolism, many of which took place in departments of pediatrics. In addition, pediatricians made important discoveries in basic genetic principles using the new somatic cell technology, such as the clonal  proof of the Lyon hypothesis by Davidson, Niitowski, and Childs and the demonstration of the  non inactivated terminal end of the shor arm of the X chromosome by Larry  Shapiro.

2.3 Molecular genetics

2003 marked the 50th anniversary f Watson and Crick’s landmark paper on the structure of DNA(Figure  1.4). This half-century has witnessed the rapid evolution of molecular genetics, culminating in 2003 in the total sequencing of the human genome. Major milestones along the genome superhighway were the description of the genetic code in 1966 by Nirenberg, the discovery of restriction enzymes and their use in mapping DNA in 1970, the invention of the Southern blot in 1975, the first cloning of human genes (chorionic somatomammotropin and the α and β chains of Hb) in 1977, the description of restriction fragment-length polymorphisms and their use in gene mapping in 1980, and the invention of PCR by Mullis in 1986. These discoveries all paved the way for the Human Genome Initiative as a multinational public and private cooperative venture, leading to the first publication of the human genome draft sequence by teams led by Francis Collins and Craig Venter in 2000.

During the past 25 y, numerous genes responsible for genetic diseases of childhood onset were identified and cloned, with such early examples as Duchenne muscular dystrophy, chronic granulomatous disease, and cystic fibrosis. These pediatric disease-based discoveries have occurred throughout the biomedical establishment not only in departments of pediatrics but also in basic science and most specialty departments in academic medical centers, as well as industry. Some of the early work in the molecular genetics of human disease was done on the hemoglobino-pathies in pediatrics departments in Boston (David Nathan and Stuart Orkin) and Baltimore (Haig Kazazian). The discovery of the genes responsible for thousands of diseases has revolutionized all of medicine and has led to the identification of their  etiologic defects, allowing new insights into methods of disease diagnosis, prevention, and treatment. It has also had a major impact on our understanding of cancer, with numerous human oncogenes and tumor suppressor genes being described, such as the genes responsible for retinoblastoma, neuro-fibromatosis, chromosome breakage syndromes, breast and ovarian cancer, colon cancer, etc. The rapid increase in  the number of diagnostic tests that could be performed by molecular techniques led to the  need to develop clinical, laboratory, and ethical standards for their wide dissemination. The American College of Medical Genetics now publishes regularly updated Standards and Guidelines for Clinical Genetics Laboratories (http://www.acmg.net). Recognizing the clinical challenges resulting from this explosion of diagnostic tests and the need for broad based public policy development to help the United States address the benefits and challenges of genetic knowledge and genetic testing, the federal government created the Secretary’s Advisory Committee on Genetic Testing in 1998, with representation from the genetics, academic laboratory, ethics, and industrial communities. In 2002, the Secretary’s Committee on Genetics, Health and Society replaced this with a broader mandate. Both committees were chaired by Edward  McCabe.

RFLPrestriction fragment length polymorphism

ADAadenosine deaminase deficiency

ASOallele-specific oligonucleotide

2.4 Common disease genetics

A great deal of work has recently been published as to the diagnosis of predisposition or susceptibility to common diseases with a genetic component. Among these are hypertension, asthma, type 2 diabetes, obesity, and psychiatric disorders, the majority of which have their clinical onset in adulthood. Although numerous associations have been reported in he literature of specific polymorphic changes in a variety of genes in some of these diseases and many others, careful analysis shows that only a small percentage of these polymorphisms are reliable diagnostic predictive markers. In addition, the ethical questions for such diagnostic screening are still under debate, especially their application to children. Nonetheless, with the development of whole genome chips over the next few years, these are very likely to become a significant component of medical practice.

3.  The role of genetics in medicine

“Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of Nature by careful investigation of cases of rare forms of diseases. For it has been found in almost all things, that what they contain of useful or applicable nature is hardly perceived; unless we are deprived of them, or they become derangedin some way.”

The recognition of the role of genetic factors in the causation of human disease has made clinical genetics one of the most rapidly developing fields in medicine. With the marked reduction in nutritional and infectious diseases in the developed countries, there has been an increasing awareness of the role of genetic determinants of human disease. Important genetic contributions to the etiology of major diseases, such as coronary artery disease, diabetes mellitus, hypertension, and the major psychoses, have been identified. At the same time, there has been a veritable explosion of knowledge in basic genetics. Much of this progress has been propelled by recent advances in the area of molecular genetics and gene mapping. Almost 600 chromosomal loci have been identified at which one or more specific disease-causing mutations have been defined. Much of this new information has been applied directly to a better understanding of the pathogenesis of disease and to improved diagnosis and management of patients. Appropriately, a major contribution of these new developments in genetics has been in the area of prevention and/or avoidance of disease, the aspect of medicine that must become the focus of modern medicine. Genetic screening programs to detect individuals at risk, improved genetic diagnosis, genetic counseling, and prenatal diagnosis are some of these current applications of new genetic knowledge to medical practice. Gene therapy trials have already begun to treat specific diseases and will have a major impact on medical practice of the future. Medical Genetics has recently become the 24th member of the American Board of Medical Specialties, the first new specialty so recognized in 12 years. Given the rapidly growing contribution of genetics to the prevention and  avoidance of clinical disease, genetic services must become an integral part of any new health care plan.

4.  Impact of genetic diseases

Contrary to common belief, many genetic diseases are far from rare and, in fact, are a significant cause of illness and death. Even those individually rare conditions are, in aggregate, a major cause of morbidity and mortality. Approximately 3% of all pregnancies result in the birth of a child with a significant genetic disease or birth defect that can cause crippling, mental retardation, or early death. A survey of more than 1 million consecutive births in British Columbia indicated that at least 1 in 20 individuals younger than 25 years of age developed a serious disease with an important genetic component. The chronic nature of many genetic diseases imposes a heavy medical, financial, and emotional burden on affected patients and their families, as well as on society at large.

Two studies of the causes of death of more than 1200 children admitted to hospitals in the United Kingdom identified genetically determined diseases as contributing 38 and 42 % of the total mortality (Table 1.1). In two North American studies of nearly 17,000 pediatric hospital admissions, clearly genetic disorders accounted for 5%~10% of the admissions. When diseases in which genetic factors are thought to play a role were included, a third to more than half of the admissions were the result of genetic disorders. Furthermore, patients with genetic diseases were hospitalized more frequently and for longer periods. Although the frequency of genetically caused diseases in the adult population is less clear, it is estimated that at least 10% of adult hospital admissions are as a result of genetic diseases. Thus, the financial and medical burdens of genetic diseases are indeed significant.

Aside from trauma, the term “nongenetic” may be a misnomer, for it is hard to conceive of any disease as being wholly nongenetic. The development of any individual depends on the interplay of genetic and environmental influences. Genetic factors are present from conception although their expression varies throughout development, whereas environmental influences are constantly changing. Since all human variation in both health and disease is to some extent genetic, all diseases are therefore genetic. Infectious diseases were once thought to represent clear examples of nongenetic diseases because specific exogenous agents of disease could be identified. However, it is now appreciated that host defense factors, many of them genetically determined, play an important role in susceptibility to infection and in the nature of the immune response to infectious agents. Thus, even in diseases with well-defined exogenous causes, genetic factors may play a critical role. More subtle examples of this same principle may be involved in the causation of such common problems as alcoholism.

The nature and extent of the genetic contribution to human variation and disease is the substance of the fields of human and medical genetics. Identification of genetic factors predisposing to disease and identification of genetically predisposed individuals are powerful keys for discovering the critical environmental agents of disease.

Paradoxically, one of the most important benefits of identifying the genetic factors in disease susceptibility may not be the potential for gene therapy, as exciting a prospect as that is, but rather the opportunity for treatment and prevention of clinical disease by manipulating the environment of individuals identified to be genetically at risk.

5.  Major types of genetic disease

Genetically determined diseases are often classified into three major categories: chromosomal, single gene defects, and polygenic, or multifactorial, diseases. Recent studies on the molecular basis of human cancer require file addition of a fourth category, somatic cell genetic defects. Each of these will be discussed briefly below and more extensively in subsequent chapters.

5.1  Chromosomal disorders

These diseases are the result of the addition or deletion of entire chromosomes or parts of chromosomes and will be discussed in detail in chapter 8. Because each chromosome contains tens of thousands of genes, physical manifestations of chromosome disorders are often quite striking. Most major chromosome disorders are characterized by growth retardation, mental retardation, and a variety of somatic abnormalities. Clinically significant chromosome abnormalities occur in nearly 1% of liveborn babies and account for about 1% of pediatric hospital admissions and 2.5 % of childhood deaths. The loss or gain of whole chromosomes is often incompatible with survival, and such abnormalities are a major cause of spontaneous abortions or miscarriages. Major chromosomal anomalies are found in almost half of spontaneous abortions. Since approximately 15 % of recognized pregnancies end in a miscarriage and it is estimated that 50% of conceptions do so, it appears that a quarter of conceptions may suffer from major chromosome problems. Thus, the major impact of chromosomal disorders occurs before birth.

A typical example of a major chromosomal disease is Down syndrome, which is caused by trisomy 21, or three copies of chromosome 21 instead of the usual two copies. This abnormality occurs in approximately 1 in 800 liveborn infants and increases in frequency with advancing mammal age. It is characterized by growth retardation, variable but often severe mental retardation, and characteristic physical abnormalities including the upward slanting eyes that have in the past given the condition the unfortunate name “mongolism.” Most significant among the congenital abnormalities associated with this condition are congenital heart defects, which are the major cause of death in children with Down syndrome. Trisomy 21 also significantly decreases intrauterine viability and the majority of affected fetuses are spontaneously aborted. Down syndrome was the first chromosomal disease defined in humans and demonstrated for the first time that alterations in chromosomal material could cause mental retardation and severe congenital anomalies. Down syndrome was also one of the first diseases amenable to prenatal diagnosis by amniocentesis.

5.2 Single gene disorders

These disorders are caused by single mutant genes with a large effect on the patient’s health. As might be expected, single gene disorders arc inherited in a simple Mendelian fashion (discussed in chapter 3) and me also referred to as Mendelian diseases. Some 6000 distinct disorders are now known to be single gene diseases inherited in autosomal dominant, autosomal recessive, or X-linked fashion. Some of these disorders will be discussed in greater detail in subsequent chapters. Single gene disorders account for approximately 5%~10% of pediatric hospital admissions and childhood mortality. The major impact of single gene disorders occurs in the newborn period and early childhood, although their importance in adult life is increasingly being appreciated. Although many single gene disorders are rare, others are common and pose major health problems. Familial hypercholesterolemia with its attendant high risk of premature coronary artery disease occurs in 1 in 500 individuals. Familial breast cancer and hereditary colon cancer each affect approximately 1 in 300. Sickle cell anemia affects 1 in 400 blacks in the United States, and cystic fibrosis affects 1 in 2000 whites. Sickle cell anemia was the first genetic disease to be defined at the molecular level, and its study serves as a model for the application of modem molecular genetic analysis to clinical disease. Single gene disorders have thus far proven to be the area in which advances in molecular genetics have made the major contribution to understanding and managing disease.

Mutations can also occur in genes on the mitochondrial chromosome, as well as in those on nuclear chromosomes. Mitochondrial diseases often affect energy production in nerve and muscle, and may play a role in cellular aging. These disorders are inherited in a uniquely maternal fashion, and are discussed in chapter 3.

5.3 Polygenic or multifactorial diseases

These diseases result from, the interaction of multiple genes, some of which may have a major effect, but many of which may have a relatively minor effect. This group of diseases is both the most common and the least understood of human genetic diseases; understanding the genetic basis of common chronic diseases represents the major challenge facing contemporary medical genetics. Examples of such polygenic diseases include the common diseases of adult life such as diabetes mellitus, hypertension, coronary artery disease, and schizophrenia, as well as a variety of common congenital defects such as cleft lip, cleft palate, and most congenital heart diseases. These diseases account for 2 5%~50% of pediatric hospital admissions, approximately 2 5%~3 5 % of childhood mortality, and because of the chronicity of many of these conditions, perhaps an even greater component of disease burden in the adult population. Thus, the clinical impact of multifactorial diseases is important in both the neonatal period and in adult life. Conceptually, this group of diseases poses tile challenge of sorting out the ways in which the additive or interactive effects of several to many genes create the predisposition to disease which in turn is manifest only in the presence of appropriate environmental triggers. It is hoped that a combination of molecular genetic approaches, gene mapping, and genetic epidemiology will allow a clearer definition of these genetic determinants and of the genetic heterogeneity underlying disease susceptibility. Models for how such interactions can cause  disease, and methods for identifying the nature and contribution of genetic factors in such diseases will be discussed in subsequent chapters.

5.4 Somatic cell genetic disorders

In contrast to the above three categories in which the genetic abnormality is found in the DNA of all cells in the body including germ cells (sperm and egg) and can be transmitted to subsequent generations, somatic cell genetic disorders arise only in specific somatic cells. The paradigm for somatic cell genetic diseases is cancer, in which development of malignancy is often the consequence of mutations in genes that control cellular growth. It is now clear that all human cancer results from mutations in DNA, making it the most common genetic disease. The various genetic mechanisms that can result in cancer are discussed in subsequent chapters.

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