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Medical genetics

 
Encyclopedia of Public Health: Medical Genetics
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Public health and medical genetics are strongly linked. The applications of both begin at preconception, when folic acid supplementation can be used to reduce birth defects, and continue through pregnancy, when testing is often done to detect abnormalities. At birth, screening of newborns for biochemical disorders enables the prevention of morbidity associated with diseases such as phenyl-ketonuria. The use of genetic screening for disorders expressed at older ages is expanding as a result of advances in molecular biology and cancer monitoring. With knowledge of the human genetic code, there will be acceleration in the diagnosis and treatment of genetic conditions and, consequently, the need for its incorporation into public health.

Classification of Genetic Disorders

The types of genetic disorders that may occur in any population can be classified into five categories:

  1. Chromosome disorders are caused by the loss, gain, or abnormal arrangement of one or more chromosomes. Their frequency in the population is about 0.2 percent. Examples include Down syndrome and Turner's syndrome.
  2. Mendelian disorders come from the mutation of a single gene. The transmission pattern is divided further into autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. The frequency is about 0.35 percent.
  3. Multifactorial disorders involve interactions between genes and environmental factors. The nature of these interactions is poorly understood. The risks of transmission can be estimated empirically, and the estimated frequency in the population is about 5 percent. Examples include cleft lip and neural tube defects.
  4. Somatic genetic disorders are not inherited but occur after conception. They often give rise to malignancies and involve environmental and genetic influences.
  5. Mitochondrial disorders arise from mutations in the genetic material in mitochondria. Mitochondrial DNA is transmitted only through the maternal line. These conditions are rare.

Chromosome Disorders

Down Syndrome. The most frequent chromosome disorder (1 in 800 births in the United States) is the one associated with Down syndrome (also called Down's syndrome or trisomy 21). A common cause of mental retardation, Down syndrome is caused, in most instances, by an extra chromosome being segregated in an egg during development. The event is random. Another cause (3 to 4% of cases) is a robertsonian translocation, in which chromosome 21 attaches to another chromosome. In this case, although the amount of genetic material is normal, the number of chromosomes is 45 instead of 46. The offspring of a parent with a robertsonian translocation have a 25 percent chance of having Down syndrome. Accordingly, karyotyping (the examination of chromosomes) is required for all children born with Down syndrome.

Down syndrome can be diagnosed during the prenatal period with amniocentesis and chorionic villous sampling. These tests involve obtaining either amniotic fluid or a sample from the placenta. Risks for Down syndrome increase with robertsonian translocation and previous birth of a child with Down syndrome; increasing maternal age; and low serum levels of maternal alpha ([.alpha])-fetoprotein (because the liver of a fetus with Down syndrome is immature, [.alpha]-fetoprotein levels are lower than normal). Further risk for Down syndrome can be ascertained by measuring the serum levels of [.alpha]-fetoprotein, estrogen, and human chorionic gonadotropin (hCG) in the blood.

Turner's Syndrome. Turner's syndrome is a disorder of growth and development occurring in about 1 in 2,000 births. The syndrome involves errors in one of the X chromosomes and is often associated with heart defects, osteoporosis, infertility, and short stature. Diabetes, hypothyroidism, and congenital urinary-tract abnormalities are also more common among patients with Turner's syndrome (35 to 70%) than in the general population. Edema before birth may cause webbing of the neck, a low posterior hairline, and ear abnormalities.

Klinefelter's Syndrome. Klinefelter's syndrome, characterized by a 47, XXY karyotype, is a disorder of growth and development, occurring in about 1.7 per 1,000 male infants. The disorder usually is diagnosed at puberty or during an infertility evaluation. In adolescents, its characteristics include gynecomastia (40%), small testicles, tall stature, and an arm span that is greater than the person's height. Klinefelter's syndrome is the most common cause of hypogonadism in males, and testosterone levels are about half the normal value, while follicle-stimulating hormone and lactate dehydrogenase levels are increased. Treatment includes testosterone, and occasionally mastectomy for gynecomastia.

Mendelian Disorders

Dominant Disorders. With classic dominant inheritance, an affected person has a parent with the same disorder. The parent usually mates with someone who does not have the genetic disorder, and the offspring have a 50 percent chance of having the disorder. Typically, predisposition for the disorder is carried on one chromosome, and expression of the disorder is modified by the chromosome makeup of the other parent. The dominant condition usually does not alter the ability to reproduce but tends to alter proteins that provide structure to a body. Examples of dominant disorders include Marfan syndrome (this has changes in the materials that give tissues strength), Huntington's disease (a degenerative nerve disease), neurofibromatosis (a disease that changes nerve structure), achondroplasia (a condition that alters cartilage), and familial hypercholesterolemia (a condition causing atherosclerosis because of increased cholesterol level). About 6 percent of cases of breast cancer are inherited dominantly.

Recessive Disorders. With classic recessive disorder inheritance, both mates have a gene for the disorder. The offspring have a 25 percent chance of having a normal gene pattern, a 50 percent chance of being a carrier, and a 25 percent chance of having the disorder. Carriers tend to have a reproductive advantage in certain environments; for example, sickle cell trait carriers are more resistant to falciparum malaria than noncarriers. The disorders tend to involve enzymes, and if siblings have the disorder it tends to be of the same severity because there is no modifying gene, as in a dominant disorder. If untreated, recessive disorders tend to cause death at an early age.

Certain nationalities are associated with recessive disorders. For example, people of Caribbean, Latin American, Mediterranean, or African descent have higher rates of sickle cell anemia or thalassemia, and those of Ashkenazi Jewish origin have higher rates of Tay-Sachs disease—and possibly Gaucher's disease (1 in 450 births). Screening is important for each of these groups.

In addition to the medical history, laboratory screening tests performed on newborns can detect recessive disorders. States require that many of these tests be performed. Examples are phenylketonuria, galactosemia, and hemoglobinopathy tests. The ideal time for conducting these laboratory studies is seventy-two hours after birth, although with early hospital dismissal of newborns, this timing is difficult. The American Academy of Pediatrics recommends that screening tests be performed in all infants before dismissal from the hospital. If the infant is dismissed less than twenty-four hours after birth, the screening tests should be repeated before the infant is two weeks old. Many medical clinics recommend rescreening if dismissal occurs at forty-eight hours, as the diagnoses of phenylketonuria and hypothyroidism may be missed if the infant is not retested after early dismissal. In some states, other screening tests are performed in newborns to detect galactosemia (with an incidence of 1 in 50,000 births, this disorder involves a defect in the enzyme for converting glucose to galactose), hemoglobinopathies, and congenital adrenal hyperplasia.

Nearly 30,000 people in the United States have cystic fibrosis, a recessive disorder. It is carried by about 1 in 25 Caucasians in the United States, and these carriers often do not have a family history of cystic fibrosis. The clinical characteristics include pancreatic insufficiency (85% of patients), pulmonary disease characterized by recurrent infections and bronchiectasis, and failure to grow. In more than 60 percent of patients, the diagnosis is made during the first year of life. The gene associated with cystic fibrosis was identified in 1989 on chromosome 7, and encodes the protein cystic fibrosis transmembrane conductance regulator (CFTR), which is a chloride channel in cells. The failure of this channel to work properly causes excess chloride in sweat and changes in fluid balance, which in turn cause thickened mucus in the lungs. The most common defect in cystic fibrosis cells is the absence of phenylalanine in the protein. Testing is recommended for patients with a family history of cystic fibrosis and their partners. There are more than 150 mutations of the cystic fibrosis gene, and testing can detect 85 percent of the carriers.

Multifactorial Disorders

Neural Tube Defects. Neural tube defects (NTDs) are the disorders most commonly screened for prenatally. The incidence of NTDs is between 1 in 1,000 and 2 in 1,000 births. A family history of NTDs and diabetes in the mother increases the risk significantly. If the mother's diet is supplemented with folic acid before conception, however, the incidence of NTDs decreases. These defects are associated with high mortality, high morbidity, and long-term developmental disability. They involve structural abnormalities of the spine, spinal cord, head, and brain.

In the United States, of every 1,000 pregnant females who are tested between 16 and 18 weeks' gestation, about 25 to 50 will have increased levels of maternal serum alpha-fetoprotein (msAFP) and 40 to 50 have low levels. The mothers with high levels of msAFP can undergo ultrasonography to assess gestational age, the presence of a multiple gestation, or significant abnormality. An alternative is to repeat the test within one to two weeks for mothers with abnormally high or low levels of the protein. If the repeat studies confirm the previous abnormal results, ultrasonography is then performed. After screening with ultrasonography, about 17 of the patients with increased levels of msAFP and 20 to 30 with low levels will have no findings that explain the abnormal values. Amniocentesis should be performed in these patients. Of the 17 patients with high levels, 1 or 2 will have a fetus with a significant NTD, whereas 1 in 65 of those with a low msAFP will have a fetus with a chromosome abnormality (1 in 90 chance of Down syndrome). For a pregnant female with an abnormally high msAFP level and a fetus with no NTD, the risk of stillbirth, low birth weight, neonatal death, and congenital anomalies is increased.

Other Disorders. The overall risk for recurrent cleft lip, with or without cleft palate, is 4 percent if a sibling or parent has the abnormality and 10 percent if it is present in two previous siblings. Lip pits or depressions on the lower lip of a newborn may be the manifestation of an autosomal dominant trait, and the recurrence rate for a sibling is 50 percent.

Generally, the incidence of multifactorial congenital disorders is less than 5 percent. The incidence of recurrence is 2 to 5 percent for cardiac anomalies, 1 to 2 percent for tracheoesophageal fistula, 1 to 2 percent for diaphragmatic hernia, 6 to 10 percent for hypospadias, and 4 to 8 percent for hip dislocation.

Prenatal Testing

In North America, about 8 percent of pregnancies meet the criteria for performing amniocentesis or chorionic villous sampling. The following are basic points for prenatal testing:

  1. All patients have the right to receive information about the genetic risk associated with a pregnancy. This allows parents to make an informed choice about having a child with an abnormality.
  2. All patients have the right to refuse testing. What a patient decides to do about any given risk factor is entirely up to the patient. Genetic testing is voluntary except for what the state requires (e.g., neonatal screening for phenylketonuria, hypothyroidism, and other inborn errors of metabolism).
  3. Genetic screening is not expected to detect all genetic disorders in a given population.

Cancer and Genetics

Certain families have an increased risk for specific cancers. Many of these families have an identifiable gene associated with the disorder. Possession of the gene does not automatically mean that cancer will develop in the patient. The expression of most genes can be altered by environmental factors and by other genes. Consequently, a risk can be predicted only on the basis of the history of the gene being found in other families. If a family has a tendency for cancer, it is prudent to consult a geneticist (a list is available from the National Society of Genetic Counselors, 233 Canterbury Drive, Wallingford, PA 19080).

Breast Cancer Genes. BRCA1, a tumor-suppressor gene, accounts for 5 to 10 percent of all cases of breast cancer. It is autosomal dominant. A woman from a family prone to breast or ovarian cancer who carries certain mutations of BRCA1 has about an 80 percent chance that breast cancer will develop and a 40 to 60 percent chance of getting ovarian cancer. Members of a family with multiple cases of breast or ovarian cancer can be tested to determine whether they have a genetic alteration in BRCA1. If such an alteration is found, presymptomatic screening could be performed on other family members as part of a research protocol. Routine screening for mutations is not reasonable because nearly 100 different mutations of this gene have been identified, many of which are unique to specific families. Certain races, such as Ashkenazi Jews (European descent), have a high incidence of a site-specific mutation on BRCA1. Screening a specific population is not feasible because the patient may have other mutations in the gene, and even if a mutation were found, the implication of a mutated BRCA1 gene in a family not prone to cancer is not known.

A BRCA2 gene has been discovered and is thought to account for other genetically linked cases of breast cancer. This gene is associated with families with a history of cancer that have a high incidence of breast cancer among male family members. Patients with the genes need follow-up. The studies include breast self-examination monthly, breast examination by a physician semiannually, and mammography annually. Ovarian surveillance includes pelvic examination, ultrasonographic visualization of the ovaries, and measurement of the serum level of CA 125 for this cancer antigen. Prophylactic bilateral mastectomy and oophorectomy also can be considered as alternatives. One study revealed a 10 percent incidence of primary peritoneal cancers after prophylactic oophorectomy.

Colorectal Cancer. The two major forms of hereditary colon cancer are hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis (FAP). Four separate genes are associated with colon cancer. Management includes annual colonoscopy beginning at age twenty-five, or when the patient is ten years younger than the youngest relative discovered to have colon cancer. Flexible sigmoidoscopy is inadequate. Women should undergo transvaginal ultrasonography or endometrial biopsy annually. FAP, characterized by the appearance of hundreds of adenomas in the large bowel, accounts for 0.5 percent of colon cancers. Colon cancer develops in virtually 100 percent of patients with untreated FAP. Removal of the colon decreases the risk to 10 percent.

The Future of Medical Genetics

Sequencing of the human genome was completed in 2000. The completion of this task will speed the development of molecular genetic recognition and treatment. Readers can obtain useful information from the list of Internet sites included.

(SEE ALSO: Environmental Determinants of Health; Genes; Genetic Disorders; Genetics and Health; Human Genome Project; Newborn Screening; Prenatal Care; Risk Assessment, Risk Management)

Bibliography

Centers for Disease Control and Prevention. Translating Advances in Human Genetics into Public Health Action: A Strategic Plan. Available at http://www.cdc.gov/genetics/publications/strategic.htm.

Columbia-Presbyterian Medical Center. "Congenital Disorders. Screening for Neural Tube Defects—Including Folic Acid/Folate Prophylaxis." In Guide to Clinical Preventive Services, 2nd edition. Available at http://www.cpmcnet.columbia.edu/texts/gcps/gcps0052.html.

Cystic Fibrosis Foundation. Facts about Cystic Fibrosis. Available at http://www.cff.org/facts.htm.

Horowitz, M., ed. (2000). Basic Concepts in Medical Genetics: A Student's Survival Guide. New York: McGraw-Hill.

Human Genome Program of the U.S. Department of Energy. "Human Genome Project Information." Available at http://www.ornl.gov/hgmis/.

National Down Syndrome Society. Education. Research. Advocacy: One Vision, One Voice. Available at http://www.ndss.org/index.html.

National Institutes of Health. "Office of Rare Diseases." Available at http://www.cancernet.nci.nih.gov/ord/genetics-info.html.

National Library of Medicine and HRSA. Gene Tests. Available at http://www.genetests.org/.

Nussbaum, R. L.; McInnes, R. R.; and Willard, H. F. Thompson and Thompson Genetics in Medicine, 6th edition. St. Louis, MO: W. B. Sanders.

Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The Genetics of Cancer. Available at http://www.cancergenetics.org/home.htm.

Turner's Syndrome Society of the United States. Available at http://www.turner-syndrome-us.org/.

University of Kansas Medical Center. Genetics and Rare Conditions Site. Available at http://www.kumc.edu/gec/support/.

— JOHN W. BACHMAN


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Medical Dictionary: medical genetics
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Home > Library > Health > Medical Dictionary

n.

The study of the etiology, pathogenesis, and natural history of diseases and disorders that are at least partially genetic in origin.

Wikipedia: Medical genetics
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Home > Library > Miscellaneous > Wikipedia
For a non-technical introduction to the topic, see Introduction to Genetics.

Medical Genetics is the specialty of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from Human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, but medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counseling of individuals with genetic disorders would be considered part of medical genetics. In contrast, the study of typically non-medical phenotypes such as the genetics of eye color would be considered part of human genetics, but not necessarily relevant to medical genetics (except in situations such as albinism). Genetic medicine is a newer term for medical genetics and incorporates areas such as gene therapy, personalized medicine, and the rapidly emerging new medical specialty, predictive Medicine.

Contents

Scope

Medical genetics encompasses many different areas, including clinical practice of physicians, genetic counselors, and nutritionists, clinical diagnostic laboratory activities, and research into the causes and inheritance of genetic disorders. Examples of conditions that fall within the scope of medical genetics include birth defects and dysmorphology, mental retardation, autism, metabolic and mitochondrial disorders, skeletal dysplasia, connective tissue disorders, cancer genetics, teratogens, and prenatal diagnosis. Medical genetics is increasingly becoming relevant to many common diseases. Overlaps with other medical specialties are beginning to emerge, as recent advances in genetics are revealing etiologies for neurologic, endocrine, cardiovascular, pulmonary, ophthalmologic, renal, psychiatric, and dermatologic conditions.

Subspecialties

In some ways, many of the individual fields within medical genetics are hybrids between clinical care and research. This is due in part to recent advances in science and technology (for example, see the Human genome project) that have enabled an unprecedented understanding of genetic disorders.

Clinical genetics

Clinical genetics is the practice of clinical medicine with particular attention to hereditary disorders. Referrals are made to genetics clinics for a variety of reasons, including birth defects, developmental delay, autism, epilepsy, short stature, and many others. Examples of genetic syndromes that are commonly seen the genetics clinic include chromosomal rearrangements, Down syndrome, DiGeorge syndrome, Fragile X syndrome, Marfan syndrome, Neurofibromatosis, Turner syndrome, and Williams syndrome.

Genetic counseling

Genetic counseling is the process through which a genetic counselor provides information about genetic conditions, diagnostic testing, and risks in other family members, within the framework of nondirective counseling.

Metabolic/biochemical genetics

Metabolic (or biochemical) genetics involves the diagnosis and management of inborn errors of metabolism in which patients have enzymatic deficiencies that perturb biochemical pathways involved in metabolism of carbohydrates, amino acids, and lipids. Examples of metabolic disorders include galactosemia, glycogen storage disease, lysosomal storage disorders, metabolic acidosis, peroxisomal disorders, phenylketonuria, and urea cycle disorders.

Cytogenetics

Cytogenetics is the study of chromosomes and chromosome abnormalities. While cytogenetics historically relied on microscopy to analyze chromosomes, new molecular technologies such as array comparative genomic hybridization are now becoming widely used. Examples of chromosome abnormalities include aneuploidy, chromosomal rearrangements, and genomic deletion/duplication disorders.

Molecular genetics

Molecular genetics involves the discovery of and laboratory testing for DNA mutations that underlie many single gene disorders. Examples of single gene disorders include achondroplasia, cystic fibrosis, Duchenne muscular dystrophy, hereditary breast cancer (BRCA1/2), Huntington disease, Marfan syndrome, Noonan syndrome, and Rett syndrome. Molecular tests are also used in the diagnosis of syndromes involving epigenetic abnormalities, such as Angelman syndrome, Beckwith-Wiedemann syndrome, Prader-willi syndrome, and uniparental disomy.

Mitochondrial genetics

Mitochondrial genetics concerns the diagnosis and management of mitochondrial disorders, which have a molecular basis but often result in biochemical abnormalities due to deficient energy production.

There exists some overlap between medical genetic diagnostic laboratories and molecular pathology.

History

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Although genetics has its roots back in the 19th century with the work of the Bohemian monk Gregor Mendel and other pioneering scientists, human genetics emerged later. It started to develop, albeit slowly, during the first half of the 20th century. Mendelian (single-gene) inheritance was studied in a number of important disorders such as albinism, brachydactyly (short fingers and toes), and hemophilia. Mathematical approaches were also devised and applied to human genetics. Population genetics was created.

Medical genetics was a late developer, emerging largely after the close of World War II (1945) when the eugenics movement had fallen into disrepute. The Nazi misuse of eugenics sounded its death knell. Shorn of eugenics, a scientific approach could be used and was applied to human and medical genetics. Medical genetics saw an increasingly rapid rise in the second half of the 20th century and continues in the 21st century.

Notable practitioners

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Current practice

The clinical setting in which patients are evaluated determines the scope of practice, diagnostic, and therapeutic interventions. For the purposes of general discussion, the typical encounters between patients and genetic practitioners may involve:

  • Referral to an out-patient genetics clinic (pediatric, adult, or combined) or an in-hospital consultation, most often for diagnostic evaluation.
  • Specialty genetics clinics focusing on management of inborn errors of metabolism, skeletal dysplasia, or lysosomal storage diseases.
  • Referral for counseling in a prenatal genetics clinic to discuss risks to the pregnancy (advanced maternal age, teratogen exposure, family history of a genetic disease), test results (abnormal maternal serum screen, abnormal ultrasound), and/or options for prenatal diagnosis (typically amniocentesis or chorionic villus sampling).
  • Multidisciplinary specialty clinics that include a clinical geneticist or genetic counselor (cancer genetics, cardiovascular genetics, craniofacial or cleft lip/palate, hearing loss clinics, muscular dystrophy/neurodegenerative disorder clinics).

Diagnostic evaluation

Each patient will undergo a diagnostic evaluation tailored to their own particular presenting signs and symptoms. The geneticist will establish a differential diagnosis and recommend appropriate testing. These tests might evaluate for chromosomal disorders, inborn errors of metabolism, or single gene disorders.

Chromosome studies

Chromosome studies are used in the general genetics clinic to determine a cause for developmental delay/mental retardation, birth defects, dysmorphic features, and/or autism. Chromosome analysis is also performed in the prenatal setting to determine whether a fetus is affected with aneuploidy or other chromosome rearrangements. Finally, chromosome abnormalities are often detected in cancer samples. A large number of different methods have been developed for chromosome analysis:

  • Chromosome analysis using a karyotype involves special stains that generate light and dark bands, allowing identification of each chromosome under a microscope.
  • Fluorescence in situ hybridization (FISH) involves fluorescent labeling of probes that bind to specific DNA sequences, used for identifying aneuploidy, genomic deletions or duplications, characterizing chromosomal translocations and determining the origin of ring chromosomes.
  • Chromosome painting is a technique that uses fluorescent probes specific for each chromosome to differentially label each chromosome. This technique is more often used in cancer cytogenetics, where complex chromosome rearrangements can occur.
  • Array comparative genomic hybridization is a new molecular technique that involves hybridization of an individual DNA sample to a glass slide or microarray chip containing molecular probes (ranging from large ~200kb bacterial artificial chromosomes to small oligonucleotides) that represent unique regions of the genome. This method is particularly sensitive for detection of genomic gains or losses across the genome but does not detect balanced translocations or distinguish the location of duplicated genetic material (for example, a tandem duplication versus an insertional duplication).

Basic metabolic studies

Biochemical studies are performed to screen for imbalances of metabolites in the bodily fluid, usually the blood (plasma/serum) or urine, but also in cerebrospinal fluid (CSF). Specific tests of enzyme function (either in leukocytes, skin fibroblasts, liver, or muscle) are also employed under certain circumstances. In the US, the newborn screen incorporates biochemical tests to screen for treatable conditions such as galactosemia and phenylketonuria (PKU). Patients suspected to have a metabolic condition might undergo the following tests:

  • Quantitative amino acid analysis is typically performed using the ninhydrin reaction, followed by liquid chromatography to measure the amount of amino acid in the sample (either urine, plasma/serum, or CSF). Measurement of amino acids in plasma or serum is used in the evaluation of disorders of amino acid metabolism such as urea cycle disorders, maple syrup urine disease, and PKU. Measurement of amino acids in urine can be useful in the diagnosis of cystinuria or renal Fanconi syndrome as can be seen in cystinosis.
  • Urine organic acid analysis can be either performed using quantitative or qualitative methods, but in either case the test is used to detect the excretion of abnormal organic acids. These compounds are normally produced during bodily metabolism of amino acids and odd-chain fatty acids, but accumulate in patients with certain metabolic conditions.
  • The acylcarnitine combination profile detects compounds such as organic acids and fatty acids conjugated to carnitine. The test is used for detection of disorders involving fatty acid metabolism, including MCAD.
  • Pyruvate and lactate are byproducts of normal metabolism, particularly during anaerobic metabolism. These compounds normally accumulate during exercise or ischemia, but are also elevated in patients with disorders of pyruvate metabolism or mitochondrial disorders.
  • Ammonia is an end product of amino acid metabolism and is converted in the liver to urea through a series of enzymatic reactions termed the urea cycle. Elevated ammonia can therefore be detected in patients with urea cycle disorders, as well as other conditions involving liver failure.
  • Enzyme testing is performed for a wide range of metabolic disorders to confirm a diagnosis suspected based on screening tests.

Molecular studies

Treatments

Each cell of the body contains the hereditary information (DNA) wrapped up in structures called chromosomes. Since genetic syndromes are typically the result of alterations of the chromosomes or genes, there is no treatment currently available that can correct the genetic alterations in every cell of the body. Therefore, there is currently no "cure" for genetic disorders. However, for many genetic syndromes there is treatment available to manage the symptoms. In some cases, particularly inborn errors of metabolism, the mechanism of disease is well understood and offers the potential for dietary and medical management to prevent or reduce the long-term complications. In other cases, infusion therapy is used to replace the missing enzyme. Current research is actively seeking to use gene therapy or other new medications to treat specific genetic disorders.

Management of Metabolic disorders

In general, metabolic disorders arise from enzyme deficiencies that disrupt normal metabolic pathways. For instance, in the hypothetical example:

    A ---> B ---> C ---> D         AAAA ---> BBBBBB ---> CCCCCCCCCC ---> (no D)
       X      Y      Z                   X           Y             (no Z)

Compound "A" is metabolized to "B" by enzyme "X", compound "B" is metabolized to "C" by enzyme "Y", and compound "C" is metabolized to "D" by enzyme "Z". If enzyme "Z" is missing, compound "D" will be missing, while compounds "A", "B", and "C" will build up. The pathogenesis of this particular condition could result from lack of compound "D", if it is critical for some cellular function, or from toxicity due to excess "A", "B", and/or "C". Treatment of the metabolic disorder could be achieved through dietary supplementation of compound "D" and dietary restriction of compounds "A", "B", and/or "C" or by treatment with a medication that promoted disposal of excess "A", "B", or "C". Another approach that can be taken is enzyme replacement therapy, in which a patient is given an infusion of the missing enzyme.

  • Diet

Dietary restriction and supplementation are key measures taken in several well-known metabolic disorders, including galactosemia, phenylketonuria (PKU), maple syrup urine disease, organic acidurias and urea cycle disorders. Such restrictive diets can be difficult for the patient and family to maintain, and require close consultation with a nutritionist who has special experience in metabolic disorders. The composition of the diet will change depending on the caloric needs of the growing child and special attention is needed during a pregnancy if a woman is affected with one of these disorders.

  • Medication

Medical approaches include enhancement of residual enzyme activity (in cases where the enzyme is made but is not functioning properly), inhibition of other enzymes in the biochemical pathway to prevent buildup of a toxic compound, or diversion of a toxic compound to another form that can be excreted. Examples include the use of high doses of pyridoxine (vitamin B6) in some patients with homocystinuria to boost the activity of the residual cystathione synthase enzyme, administration of biotin to restore activity of several enzymes affected by deficiency of biotinidase, treatment with NTBC in Tyrosinemia to inhibit the production of succinylacetone which causes liver toxicity, and the use of sodium benzoate to decrease ammonia build-up in urea cycle disorders.

Certain lysosomal storage diseases are treated with infusions of a recombinant enzyme (produced in a laboratory), which can reduce the accumulation of the compounds in various tissues. Examples include Gaucher disease, Fabry disease, Mucopolysaccharidoses and Glycogen storage disease type II. Such treatments are limited by the ability of the enzyme to reach the affected areas (the blood brain barrier prevents enzyme from reaching the brain, for example), and can sometimes be associated with allergic reactions. The long-term clinical effectiveness of enzyme replacement therapies vary widely among different disorders.

Other examples

  • Angiotensin receptor blockers in Marfan syndrome & Loeys-Dietz
  • Bone marrow transplantation
  • Gene therapy

Career paths and training

There are a variety of career paths within the field of medical genetics, and naturally the training required for each area differs considerably. It should be noted that the information included in this section applies to the typical pathways in the United States and there may be differences in other countries. US Practitioners in clinical, counseling, or diagnostic subspecialties generally obtain board certification through the American Board of Medical Genetics.

Career Degree Description Training
Clinical Geneticist MD or MD/PhD A Clinical geneticist is typically a physician who evaluates patients in the office or as a hospital consultation. This process includes a medical history, family history (pedigree), a detailed physical examination, reviewing objective data such as imaging and test results, establishing a differential diagnosis, and recommending appropriate diagnostic tests. College (4 yrs) → Medical school (4 yrs) → Primary residency (2-3 yrs) → Residency in Clinical genetics (2 yrs). Some Clinical geneticists also obtain a PhD degree (4-7 yrs). A new residency track offers a 4 yr primary residency in Clinical genetics immediately after finishing Medical school.
Genetic Counselor MS A Genetic counselor specializes in communication of genetic information to patients and families. Genetic counselors often work closely with Clinical geneticists or other physicians (such as Obstetricians or Oncologists) and often convey the results of the recommended tests. College (4 yrs) → Graduate program in Genetic counseling (2 yrs).
Metabolic nurse and/or nutritionist BA/BS, MS, RN One of the critical aspects of the management of patients with metabolic disorders is the appropriate nutritional intervention (either restricting the compound that cannot be metabolized, or supplementing compounds that are deficient as the result of an enzyme deficiency). The metabolic nurse and nutritionist play important roles in coordinating the dietary management. College (4 yrs) → Nursing school or graduate training in nutrition.
Biochemical Diagnostics PhD, MD, or MD/PhD Individuals who specialize in Biochemical genetics typically work in the diagnostic laboratory, analyzing and interpreting specialized biochemical tests that measure amino acids, organic acids, and enzyme activity. Some Clinical Geneticists are also board certified in Biochemical Genetics. College (4 yrs) → Graduate school (PhD, usually 4-7 years) and/or Medical school (MD, 4 years)
Cytogenetic Diagnostics PhD, MD, or MD/PhD Individuals who specialize in Cytogenetics typically work in the diagnostic laboratory, analyzing and interpreting karyotypes, FISH, and comparative genomic hybridization tests. Some Clinical Geneticists are also board certified in Cytogenetics. College (4 yrs) → Graduate school (PhD, usually 4-7 years) and/or Medical school (MD, 4 years)
Molecular Diagnostics PhD, MD, or MD/PhD Individuals who specialize in Molecular genetics typically work in the diagnostic laboratory, analyzing and interpreting specialized genetic tests that look for disease-causing changes (mutations) in the DNA. Some examples of molecular diagnostic tests include DNA sequencing and Southern blotting. College (4 yrs) → Graduate school (PhD, usually 4-7 years) and/or Medical school (MD, 4 years)
Research Geneticist PhD, MD, or MD/PhD Any researcher who studies the genetic basis of human disease or uses model organisms to study disease mechanisms could be considered a Research Geneticist. Many of the clinical career paths also include basic or translational research, and thus individuals in the field of medical genetics often participate in some form of research. College (4 yrs) → Graduate school (PhD, usually 4-7 years) and/or Medical school (MD, 4 years) → Post-doctoral research training (usually 3+ years)
Laboratory Technician BS or MS Technicians in the diagnostic or research labs handle samples and run the assays at the bench. Often these individuals are promoted to supervisory positions. College (4 yrs), may have higher degree (MS, 2+ years)

Ethical, legal and social implications

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Genetic information provides a unique type of knowledge about an individual and his/her family, fundamentally different than a typically laboratory test that provides a "snapshot" of an individual's health status. The unique status of genetic information and inherited disease has a number of ramifications with regard to ethical, legal, and societal concerns.

5.1 Genetic discrimination

5.2 Patient confidentiality vs. the Physician's duty to warn

5.3 Determinism vs. predisposition

5.4 Prenatal testing

Societies

The more empirical approach to human and medical genetics was formalized by the founding in 1948 of the American Society of Human Genetics. The Society first began annual meetings that year (1948) and its international counterpart, the International Congress of Human Genetics, has met every 5 years since its inception in 1956. The Society publishes the American Journal of Human Genetics on a monthly basis.

Medical genetics is now recognized as a distinct medical specialty in the U.S. with its own approved board (the American Board of Medical Genetics) and clinical specialty college (the American College of Medical Genetics). The College holds an annual scientific meeting, publishes a monthly journal, Genetics in Medicine, and issues position papers and clinical practice guidelines on a variety of topics relevant to human genetics.

Research

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The broad range of research in medical genetics reflects the overall scope of this field, including basic research on genetic inheritance and the human genome, mechanisms of genetic and metabolic disorders, translational research on new treatment modalities, and the impact of genetic testing

Basic genetics research

Basic research geneticists usually undertake research in universities, biotechnology firms and research institutes.

Disease mechanisms

Translational research

Impact of genetic testing

Other

Allelic architecture of disease

Main article: Population groups in biomedicine

Sometimes the link between a disease and an unusual gene variant is more subtle. The genetic architecture of common diseases is an important factor in determining the extent to which patterns of genetic variation influence group differences in health outcomes.[1] According to the common disease/common variant hypothesis, common variants present in the ancestral population before the dispersal of modern humans from Africa play an important role in human diseases.[2] Genetic variants associated with Alzheimer disease, deep venous thrombosis, Crohn disease, and type 2 diabetes appear to adhere to this model.[3] However, the generality of the model has not yet been established and, in some cases, is in doubt.[4] Some diseases, such as many common cancers, appear not to be well described by the common disease/common variant model.[5]

Another possibility is that common diseases arise in part through the action of combinations of variants that are individually rare.[6] Most of the disease-associated alleles discovered to date have been rare, and rare variants are more likely than common variants to be differentially distributed among groups distinguished by ancestry.[7] However, groups could harbor different, though perhaps overlapping, sets of rare variants, which would reduce contrasts between groups in the incidence of the disease.

The number of variants contributing to a disease and the interactions among those variants also could influence the distribution of diseases among groups. The difficulty that has been encountered in finding contributory alleles for complex diseases and in replicating positive associations suggests that many complex diseases involve numerous variants rather than a moderate number of alleles, and the influence of any given variant may depend in critical ways on the genetic and environmental background.[8] If many alleles are required to increase susceptibility to a disease, the odds are low that the necessary combination of alleles would become concentrated in a particular group purely through drift.[9]

Population substructure in genetics research

Further information: Human genetic clustering

One area in which population categories can be important considerations in genetics research is in controlling for confounding between population substructure, environmental exposures, and health outcomes. Association studies can produce spurious results if cases and controls have differing allele frequencies for genes that are not related to the disease being studied,[10] although the magnitude of this problem in genetic association studies is subject to debate.[11] Various methods have been developed to detect and account for population substructure,[12] but these methods can be difficult to apply in practice.[13]

Population substructure also can be used to advantage in genetic association studies. For example, populations that represent recent mixtures of geographically separated ancestral groups can exhibit longer-range linkage disequilibrium between susceptibility alleles and genetic markers than is the case for other populations.[14] Genetic studies can use this admixture linkage disequilibrium to search for disease alleles with fewer markers than would be needed otherwise. Association studies also can take advantage of the contrasting experiences of racial or ethnic groups, including migrant groups, to search for interactions between particular alleles and environmental factors that might influence health.[15]

Textbooks and journals

See also

External links

References

  1. ^ Reich DA, Lander ES, "On the allelic spectrum of human disease," Trends Genet (2001) 17: 502–510; Pritchard JK, Cox NJ, "The allelic architecture of human disease genes: common disease-common variant...or not?," Hum Mol Genet (2002) 11: 2417–2423; Smith DJ, Lusis AJ, "The allelic structure of common disease," Hum Mol Genet, (2002) 11: 2455–2461.
  2. ^ Goldstein DB, Chikhi L, "Human migrations and population structure: what we know and why it matters," Ann Rev Genomics Hum Genet, (2002) 3: 129–152.
  3. ^ Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN, "Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease," Nat Genet (2003) 33: 177–182.
  4. ^ Weiss KM, Terwilliger JD, "How many diseases does it take to map a gene with SNPs?," Nat Genet (2000) 26: 151–157; Pritchard JK, Cox NJ, "The allelic architecture of human disease genes: common disease-common variant...or not?," Hum Mol Genet (2002) 11: 2417–2423; Cardon LR, Abecasis GR, "Using haplotype blocks to map human complex trait loci," Trends Genet (2003) 19: 135–140.
  5. ^ Kittles RA, Weiss KM, "Race, ancestry, and genes: implications for defining disease risk," Annu Rev Genomics Hum Genet (2003) 4: 33–67.
  6. ^ Pritchard JK, "Are rare variants responsible for susceptibility to complex diseases?," Am J Hum Genet (2001) 69: 124–137; Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH, "Multiple rare alleles contribute to low plasma levels of HDL cholesterol," Science (2004) 305: 869–872.
  7. ^ Risch N, Burchard E, Ziv E, Tang H, "Categorization of humans in biomedical research: genes, race and disease," Genome Biol (2002) 3 (http://genomebiology.com/2002/3/7/comment/2007) (electronically published July 1, 2002; accessed August 25, 2005); Kittles RA, Weiss KM, "Race, ancestry, and genes: implications for defining disease risk," Annu Rev Genomics Hum Genet (2003) 4: 33–67.
  8. ^ Risch N, "Searching for the genetic determinants in a new millennium," Nature (2000) 405: 847–856; Weiss KM, Terwilliger JD, "How many diseases does it take to map a gene with SNPs?," Nat Genet (2000) 26: 151–157; Altmüller J, Palmer LJ, Fischer G, Scherb H, Wjst M, "Genomewide scans of complex human diseases: true linkage is hard to find," Am J Hum Genet (2001) 69: 936–950; Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K, "A comprehensive review of genetic association studies," Genet Med (2002) 4: 45–61.
  9. ^ Cooper RS, "Genetic factors in ethnic disparities in health," in Anderson NB, Bulatao RA, Cohen B, eds., Critical perspectives on racial and ethnic differences in health in later life, (Washington DC: National Academy Press, 2004), 267–309.
  10. ^ Cardon LR, Palmer LJ, "Population stratification and spurious allelic association," Lancet (2003) 361: 598–604; Marchini J, Cardon LR, Phillips MS, Donnelly P, "The effects of human population structure on large genetic association studies," Nat Genet (2004) 36: 512–517.
  11. ^ Thomas DC, Witte JS, "Point: population stratification: a problem for case-control studies of candidate-gene associations?" Cancer Epidemiol Biomarkers Prev (2002) 11: 505–512; Wacholder S, Rothman N, Caporaso N, "Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer," Cancer Epidemiol Biomarkers Prev (2002) 11 :513–520.
  12. ^ Morton NE, Collins A, "Tests and estimates of allelic association in complex inheritance," Proc Natl Acad Sci USA, (1998) 95: 11389–11393; Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM, "Control of confounding of genetic associations in stratified populations," Am J Hum Genet (2003) 72: 1492–1504.
  13. ^ Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, Altshuler D, "Assessing the impact of population stratification on genetic association studies," Nat Genet (2004) 36: 388–393.
  14. ^ Hoggart CJ, Shriver MD, Kittles RA, Clayton DG, McKeigue PM, "Design and analysis of admixture mapping studies," Am J Hum Genet (2004) 74: 965–978; Patterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR, Hauser SL, Smith MW, O'Brien SJ, Altshuler D, Daly MJ, Reich D, "Methods for high-density admixture mapping of disease genes," Am J Hum Genet, (2004) 74: 979–1000; Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A, Kessing BD, et al., "A high-density admixture map for disease gene discovery in African Americans," Am J Hum Genet (2004) 74: 1001–1013; McKeigue PM, "Prospects for admixture mapping of complex traits," Am J Hum Genet, (2005) 76: 1–7.
  15. ^ Chaturvedi N, "Ethnicity as an epidemiological determinant—crudely racist or crucially important?" Int J Epidemiol (2001) 30: 925–927; Collins FS, Green ED, Guttmacher AE, Guyer MS, for the US National Human Genome Research Institute, "A vision for the future of genomics research," Nature (2003) 422: 835–847.
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