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  • Human Genetics: The Keys to Our Existence

    Edwin M. Knights Jr., M.D.

    Published Date : April 3, 2007

    Our paired chromosomes consist of two very long DNA molecules combined with proteins, and our genes are located at intervals along these chromosomes. A major function of genes is to synthesize essential proteins. In general, the pairs of chromosomes carry similar information, with the same genes, but there are variations of the nucleotide bases in each gene. Different variants of a gene are called alleles.

    If one gene of a pair is defective, the other one may code for enough protein so that the abnormality isn't clinically apparent. In this case the abnormality is called recessive. If the abnormality is clinically apparent, it is called a dominant hereditary disorder. A person with one abnormal gene is heterozygous for that gene. A child who inherits an abnormal recessive gene from each parent is homozygous for that gene.

    Single-gene disorders, such as were described by that most famous of all pea-pickers, Gregor Mendel, are actually quite unusual in humans, in less than 1 in 500 births. The first person to be recognized as having the phenotype (appearance) of a singe-gene disorder is called the proband; the pattern of genetic transmission through succeeding generations is called a pedigree. And the four basic patterns of single gene inheritance are autosomal dominant, autosomal recessive, X-linked dominant and X-linked recessive. A phenotype that is expressed in both heterozygotes and homozygotes is dominant.

    A phenotype expressed only in homozygotes is recessive. It is also recessive if it is X-linked but expressed only in males. Heterozygotes having a recessive abnormal gene (but not usually expressing the abnormal phenotype) are called carriers.

    When single-gene disorders are inherited by autosomal dominance, the associated abnormalities appear in every generation. Each child of an affected parent has a 50 percent chance of having the disease. It is transmitted by both males and females, while normal parents don't transmit the disease.

    In autosomal recessive inheritance, frequently the parents don't present the phenotype of the disease. In this type of inheritance, the odds of a child inheriting the disease are 1 in 4, but in order for the disease to be symptomatic, the atypical genes have to be transmitted by both parents.

    In X-linked dominant inheritance, it just takes one of the two X genes to be defective for the disease to be manifest in a female. Since males pass their Y chromosome to their sons, affected males, known as hemizygous males, don’t have affected sons but every daughter will be affected. Sons or daughters of affected females each have a 50 percent chance of being affected.

    In X-linked recessive inheritance, the disease appears much more often in males. Since the abnormal gene is on the X-chromosome, males don’t pass the disease on to their sons but they do so to every daughter. As the trait is recessive, these daughters will be carriers but won’t have the abnormal genetic phenotype. Their sons and daughters will have a 50 percent chance of inheriting the defective gene.

    As we will see, many common diseases of humans don’t follow the relatively simple mendelian inheritance patterns. Instead, diseases are the result of complex interactions among several or even numerous genes. Early myocardial infarction can result from hypertension, which has multiple possible genetic causes, and from increases in certain serum lipids controlled by other genes. This may result in the development of atherosclerosis, with narrowing of coronary arteries by calcified plaques. Other genes involving clotting factors and the adhesion of blood platelets may contribute to the development of an occluding thrombus which blocks the narrowed coronary artery and causes the myocardial infarction. Further adding to the complexity of the clinical picture are what for lack of a better description are called environmental effects. Some of these, such as obesity, lack of proper exercise an smoking are major contributors to heart disease. And in some diseases, the environmental causes clearly outweigh the genetic influences.

    When entire chromosomes are affected, rather than single or multiple genes, major heritable abnormalities result. Down syndrome, in which there is an extra chromosome 21, is the most common of these disorders (1/800). Other fairly common chromosomal disorders include Klinefelter’s syndrome (1/1,000 males) and Turner’s syndrome (1/5,000 females).

    Mitochondria are little non-nuclear power plants located in the cytoplasm of your cells, very involved with production of energy through a process known as oxidative phosphorylation. They have their own DNA, which is transmitted unchanged from a mother to each of her offspring. The diseases caused by mutations in mitrochondrial DNA (mtDNA) involve entire systems and tend to affect those organs which need the most energy.

    Creating a Medical History Chart
    A chart of your family’s medical history is really a family tree which includes important information needed to trace heritable diseases in your family. It is called a pedigree pattern, and you can construct it yourself on a large sheet of paper, or if you are talented, in your computer. It will consist of names or little boxes arranged to show the family relationships together with a few pertinent statistics. If there is additional data that you feel might be important, don’t try to cram it into the little box, but use a number to indicate a footnote or longer reference.

    Ref: Figures l, 2, 3 and 4: Pedigree patterns of ineritance. Dominant phenotypes are apparent, but carriers or recessive traits don’t show. Figure 5 is from Newman, John H. et al., Mutation in the gene for bone morphogenetic protein receptor 11 as a cause of primary pulmonary hypertension in a large kindred. N. Engl J Med 2001; 345:319-24. It shows an abbreviated pedigree of a large kindred comprising five subfamilies over seven generations and 394 known descendants of generation 1, showing the heritability of sporadic pulmonary hypertension associated with mutation in BMPR2. Note the use of standard genetic symbols to identify male and female diseased and carrier family members.

    The footnote for each box needs to contain as much as possible of the following items:

      Relationship to you: e.g., mother, mother’s sister, maternal female cousin, etc.
      Name: full name; include maiden name of a wife in brackets
      Ethnicity: many heritable diseases predominate in ethnic groups
      Date and place of birth
      Date and place of death
      Cause of death
      Diseases, physical or mental defects: date diagnosed?
      Occupation: or other significant environmental factors

    If you are tracing a particular heritable condition, placing a flag or marker in the boxes of the affected relatives will make it easier to interpret the pedigree pattern. And if you have evidence someone was a carrier of a disease, be sure to note it in the box.

    Any two people who’ve produced children should be located horizontally on the chart, joined by a horizontal line. Indicate that couple’s children with vertical lines. If there are multiple spouses, be sure they are all listed, even if they did not produce children , and be sure the children are connected to the correct spouse!

    First degree relatives would be parents, brothers, sisters and children. Blood relatives who are two lines away are considered second-degree relatives, such as grandparents, aunts and uncles, neices and nephews, and half-siblings. It is important to include information on as many of these as possible. In other words, give them the third degree, because as you will see, the familial inheritance patterns differ in dominant and recessive conditions and the inheritance influenced by genes located on the X or Y sex chromosomes. Figure 6 Represents the hypothetical family medical pedigree of Mark A. Chad and his wife, Dymple A. Chad. Known cases of a heritable disease can then be represented by symbols; genetic analysis could identify carriers.

    From one-third to one-half of diseases are inherited, but the modes of inheritance differ greatly, as do the effects of environment. In some cases you just inherit susceptibility to a disease and environmental factors may play a greater role in determining whether you actually acquire the disease. The age of onset can be a clue, as many of the inherited diseases show up at birth or in childhood. Also, if a parent had a heart attack a age 50 or a close relative had breast cancer at age 45, you may be at risk for these conditions. A good time to start researching medical history is at family gatherings. It can save a lot of time and energy to learn about your grandparents, great uncles and aunts from other relatives. And don’t just ask about the cause of death. There is so much genetic research going on that even the medical experts aren’t exactly sure how important heritage is in some of the most common diseases and what might be available in the future to prevent them. Everybody talks about cancer and heart disease, but how about cataracts? Was either grandparent blind or did they have cataract surgery? And diabetes? If any relatives were diabetics, you need to find out whether it was type 1, early onset; type 2, adult onset; or perhaps one of the other varieties. Such common conditions as gout, psoriasis, melanoma, even colorblindness all have heritable links, some weak and some very strong, which may one day make early diagnosis and treatment possible.

    You’ll note that ethnicity is right up near the top of the list of items you’ll want to document. It’s there because in finding familial diseases you can play the odds, and the odds can be very much in your favor, or perhaps disfavor. Here’s a good example: Do any members of your family have problems when they consume milk products? Or in scientific jargon, do they have lactose intolerance? If they drink a lot of milk or devour delicious scoops of ice cream do they develop abdominal cramps, bloating, flatulance or diarrhea? If this happens, it doesn’t necessarily mean they are abnormal, In fact, some would argue they are normal. Why? It’s mostly likely because of an ethnic background. About three-quarters of the adults in the world react the same way they do, because they lost the ability to digest lactose after they were weaned. These include most of those with Asian, African and Native American backgrounds, but also people with Italian, Greek, Arab and Jewish ancestry.

    This might diagnosis one of your family’s medical problems already. That doesn’t mean you’ve solved it, of course, but since Northern Europeans probably mutated a gene long ago to enable them to drink milk, maybe scientists will some day be able to duplicate the mutation for future generations.

    Predisposition to develop the type 2, adult onset diabetes is not only familial but also affects larger ethnic groups, including Native Americans and Hispanics. Some Pima Native Americans have a 40 percent rate of diabetes, but it is strongly influenced by diet and life style. Diabetes also affects about a third of the natives of the Pacific island of Nauru and at least one of the outer islands of Indonesia. One aberrant gene for type 2 diabetes has been found in Finnish families. The genetic risk in Caucasians is fairly low, but diet, obesity, and life style are causing an increase in cases.

    Cystic fibrosis carriers and mutation rates in ethnic groups are shown in tables elsewhere in this book. The most frequent carriers of DNA mutants are Caucasians and Ashkenazi Jews.

    The Jewish community is very active in researching their genetic traits and constitute an excellent resource for information and support organizations. publications include:

    Genetic Diversity Among Jews - Diseases and Markers at the DNA Level
    Jewish Genetic Disorders: A Layman’s Guide

    Information is offered about genetic counseling and screening, plus the following heritable genetic conditions:

    Bloom’s Syndrome Familial Mediterranean Fever
    Breast Cancers Fanconi Anemia
    Canavan Disease Gaucher Disease
    Crohn’s Disease Machado Joseph Disease
    Colon Cancer Neimann-Pick
    Cystic Fibrosis Tay-Sachs Disease
    Fabry Disease Ulcerative Colitis
    Familial Dysautonomia

    There are a number of anemias with ethnic relationships. One of the more common is pernicious anemia, which is most common in people of Scandinavian, English and Irish ancestry. It is less common in those of Italian or Greek descent and rare in Blacks and Asians.

    Sickle cell trait or anemia is mostly in those of Mediterranean and African ancestry and affects 50,000 Americans. The most common varieties are sickle cell anemia (Hb SS), a combination with HbC (HB SC), Hb S/beta-thalassemia, and the sickle cell trait (Hb AS). There are at least 476 beta globin gene variants. (Ref: The frequency of most of these variants in ethnic groups represented in a California newborn population shows Hb AS to be highest in Blacks, at 1/14; in Native Americans and Hispanics it is next most common, at 1/176 and 1/185.

    Alpha thalassemia affects mainly persons of Southeast Asian, Chinese and Filipio ancestry. There is also an internet-based record of carriers of the beta-thalassemia trait organized by Stanley Diamond.

    Table 1 shows ethnic groups and some of the genetic statistics that are available. Obviously data is incomplete, always being revised and deserves your critical evaluation.

    Among the other ethnic groups which have received special attention because they have remained relatively self-contained, with minimal genetic dilution, are the Acadians, the French settlers who were exiled from the maritime portion of what later became Canada and settled in the Louisiana Territory. The Amish also marry within their community and keep detailed family records going back many generations. Research includes study of the prevalence of diabetes. And the population of Iceland has been a gold mine of genealogical treasure for genomic investigation, including the finding of a genetic association with late-onset Parkinson disease.

    Of course most of the genetic research, as you will see elsewhere in this book, is focusing on common conditions, such as cancer of the breast, colon and prostate, or persons at risk to develop high blood pressure or have heart attacks at an early age. As they have already identified genes which predispose a person to developing these conditions, many families will benefit greatly by knowing they could be at risk and taking measures to prevent a disease, or at least diagnose it when it is in an early stage and can be completely cured. In some cases, just changing one’s life style and eating habits can pay huge dividends.

    Nearly all published work on ethnicity and heritable disorders deals with the subject disease by disease. The best evidence comes from population-based studies which are least biased in their selection of subjects. This presentation is of great value to those whose interests are focused on a particular disease or syndrome, but it provides very little useful information to a genealogists who asks, "Is my family at risk for any particular diseases?" If we include ethnicity as a part of the documentation in a family medical history, then we should provide a means for rendering that information easier to access. Table 1 lists various ethnic groups upon which population or family research studies have been performed and the conclusions that have been drawn by the investigators and others.

    Bear in mind that ethnicity is far from perfect, but it is about as close as we can come with large groups of individuals who have intermingled over the history of mankind. It is far better than using the term "race," because molecular genetic scientists all agree now that there is only one race, which is the human race. Even the United States Census, which uses the term, admits that is is perpetuating American mythology by using definitions which are socially and politically, rather than scientifically established. The Hispanics, for example, represent a population which originated at one time in Spain, but already included two Mongol tribes, Arabs from the Middle East, and Sephardic Jews. Expand it to include Central and South America, which Spain and Portugal colonized, and we then mix in Native Americans and African Blacks.

    If you are reviewing a certain ethnic group is is also well to recognize that published research studies dealing with the occurrence of a disorder in that group do not necessary imply that particular disorder is uniquely prevalent or poses a particular risk to everyone else of that ethnic background. Indeed, the study may have found a higher incidence in some other group. It does show that the disorder actually occurs and may suggest the degree of risk. Sometimes investigators have found one or two families or an isolated colony within a population and carried out extensive investigations of a particular disease, but there is no evidence that the majority of people in that population are necessarily at increased risk.

    Certain ethnic groups have been the object of far more genetic research than others, as we noted in mentioning the Acadians, the Amish and Icelanders. The ethnic Jewish subpopulation which seems to have received the most genetic scrutiny are the Ashkenazi Jews, representing a segment of the Jewish population in which local customs, traditions and religious beliefs resulted in a very homogeneous genetic picture. Some Native American groups are also relatively undiluted by other genes, as are populations of some small, isolated islands in the Pacific Ocean. There are islands in the Indonesian archipelago which have high percentages of cleft palates or diabetes, but findings on these islands cannot be extrapolated to include even nearby islands.

    When medical students are introduced to the subject of pharmacology, they soon realize that individuals respond differently to medications and the concept of a standard dose can end up providing ideal therapy in one patient and an inadequate response or a distressing toxic reaction in another. Even when pharmacologists used to use cats to determine the dosage of digitalis for patients with heart disease, the pharmacology professor used to warn the class that a Chicago alley cat didn’t always react similarly to one that prowled the pavements of Manhattan.

    Individualizing therapy has always been part of the art, rather than the science of medicine, as the physician took into consideration the patient’s age, weight, eating and drinking habits plus a little shrewd guessing based upon past experience to approximate the appropriate dosage. In some cases, the therapeutic response is easily evaluated, as indicated by a useful laboratory test for glucose or a proper blood pressure level. In other situations, there may be a need for follow-up communication with the patient about subsequent improvement or deterioration of the clinical status. In the worst cases, the patient’s life may depend upon prompt realization of the desired effects.

    Molecular genetic research on the response to drugs concentrates on the mechanisms involved. Some genes make enzymes which determine how you absorb, metabolize and eliminate drugs. Some genes manufacture receptors on cell surfaces where drugs must dock in order to become effective. And genetic changes within cells can make them susceptible to some drugs but resistant to others. By studying all three of these possible responses to drugs, treatment can be made more efficient, safer and better suited to the needs of the patient. This is a radical departure for drug manufacturers, whose objectives have been to make the most profit by marketing drugs to benefit the most people. This new approach is to make the most profit by producing the maximum benefit for a minority of the people, but saving the lives of some of 100,000 Americans they claim die annually from adverse drug reactions. The validity of that figure is open to question, but there is no doubt that "personalized" pharaceuticals will reduce risks and enhance results.

    The term "personalized" is somewhat misleading, because many of the genetic aberrations are not that unique, with some of them involving families or even entire ethnic groups. Consider, for example, the genes for the cytochrome P-450 enzymes. These genes make enzymes which metabolize about half of all the drugs now in common use, carrying them around, making them functional and controlling their excretion. One of these genes is CYP2D6 and it is a busy enzyme, being responsible for such diverse matters as the metabolism of beta blockers (like carvedilol, used for heart disease), metabolizing codeine to morphine, and also breaking down tricyclic antidepressants and selective serotonin reuptake inhibitors (such as Prozac).

    CYP2D6 is functionally absent from 8 percent of whites but less than 1 percent of Asians. Although almost absent from white and Asian populations, many African Americans have another CYP2D6 allele that impairs the activity of an enzyme affecting the metabolism of the beta-blocker carvedilol. Patients having either of these types of CYP2D6 could be subject to overdosage of a beta-blocker. Others with only the first variant could fail to excrete tricyclin antidepressant or drugs like Prozac and thus not be able to get pain relief from codeine.

    Another example of ethnic-based pharmacogenetic variations is CPY2C19; its distribution contrasts with CYP2D6 in that it is found in less than 2 percent of whites but common in Asians (18-20 percent). It is another allele causing poor metabolism, in this case of omeprazole, a drug doctors employ to eliminate bacteria known as Helicobacter pylori from peptic ulcer patients. Still another variant, CYP2C9, affects the usefulness of warfarin as an anticoagulant.

    And there are more: TPMT is another genetic factor needed to metabolize 6-mercaptopurine, a thiopurine drug which is used in leukemia chemotherapy. Variants of beta 2AR can either increase or decrease reponse to the asthma drug albuterol. Another enzyme-producing gene, ACE, is said to enhance response to the beta-blockers used by physicians for cardiac problems.

    These are but some of the applications of molecular pathology demonstrating that drug response, while affecting the individual patient, can represent broad ethnic genetic distribution rather than being individual or familial phenomena. As more research results become known, significant genetic patterns among whites, African-Americans and Asians are becoming apparent. Genetic variations, or SNPs, can be used as tools to predict a person’s response to various drugs. Traditional gene sequencing technology is too inefficient to use for diagnostic purposes. Instead, the use of chips with DNA microarrays can screen thousands of SNPs from a patient’s genome in a few hours. Drug companies will benefit greatly from SNP screenings because they will be able to exclude subjects in which a drug might be inefficient or harmful and speed up clinical trials on the appropriate persons. Clinicians will also benefit, because eventually it will be possible to profile patients rapidly prior to starting treatment, adjusting therapy and dosage to balance the absorption, metabolism and elimination of the most appropriate drugs.

    Also to be seriously considered are the non-genetic factors usually lumped under the term “environmental," which can contribute anywhere from minimal to maximal influence as to whether a potential genetic disorder will materialize into an actual disease. One long-recognized example of this involved Japanese predisposition to gastric cancer. This statistic applies to those Japanese who live in Japan and those who recently migrated to the United States, but the incidence of gastric cancer drops sharply in subsequent generations. A similar contrast has been found in Pima Indians living in different locations with very different life styles, as they have markedly differing percentages afflicted with type 2 diabetes mellitus. Type 2 diabetes has generally been a low risk in Caucasians, but currently there has been a dramatic increase in the disease in the United States. It is being attributed to diet, obesity and lack of exercise, as the younger population has managed to switch the odds against themselves.

    Any decisions concerning genetic testing, therefore, must be based upon carefully weighted individual circumstances. If there is evidence previously garnered from high-risk families which have a similar inheritance pattern to the one under investigation, such knowledge may be very useful in helping to arrive at a decision about whom to test and just what documentation is needed. Long before genetic testing was widely available, chromosome studies were deemed to be indicated in certain clinical conditions, but even before these were considered, a careful review was made of the clinical history, physical findings, and the results obtained by other appropriate procedures. These could include relatively inexpensive screening tests used to identify “inborn errors of metabolism," X-rays, ultrasound, or even needle biopsies. Table 3 shows the clinical approach to assess or ruling out some heritable conditions.

    In evaluating evidence, be sure to consider the relevance of evidence as it affects each family member and calculate the current risk and future risk to any descendants. Publishing your family’s experiences in dealing with genetic pedigree findings would be most valuable for other families in similar predicaments. Unfortunately, because of apprehension about the confidentiality and security of medical records, such information isn’t widely available. It may be possible to present such material as that of an anonymous family so there is no possibility of recognition of specific individuals.

    Now that you may have some hints from the family gathering and from your ethnic research, it is time to interview any available family members for your genealogical project. If they understand that your objectives are purely medical and concern the health and welfare of children and future members of the family, you may get better cooperation. It is well to make a check list of items you wish to cover, so you won’t get side-tracked and miss some invaluable clues. You can’t just rely upon asking about specific diseases, because frequently the relatives only know the history and course of the disease but never knew what it was called. Each disease has a characteristic history, symptoms and physical physical findings and runs a typical course, perhaps modified or prolonged by medical or surgical intervention. Write down your findings, especially phrases or words you don’t recognize because they are no longer in common use. “Dropsy" or “lumbago" can all be found if you look in the right places. In general, trying to talk to a family doctor, unless you are next of kin, is not going to be very productive. It’s not just that they are so busy but that confidentiality of medical records receives strong legal protection. Also, living in a litigous society, they are wary of relatives being urged on by an unscrupulous attorney seeking a frivolous lawsuit.

    Death certificates are designed for public health purposes, not for genealogists, and unless there was a coronor’s inquiry or the relative died in a hospital and was autopsied, the “cause of death" can be misleading, at best. Some states keep the death certificates confidential for considerable time, but eventually the death certificate should be a part of every genealogical record, because it contains valuable information about age, place of birth, parents, and address even if the “final diagnosis" is misleading.

    Funeral home records can be excellent or terrible; if you find good ones, you are in luck. Many funeral homes start as family businesses, then are sold locally or become affiliated with large organizations. As in any other business, record keeping often suffers during transition. Cemetery records are usually reliable, and finding a family plot can “unearth" relatives you never knew existed, but tombstones don’t usually help much with diagnosing familial diseases. Having inherited a small cemetery in the distant corner of an 80 acre farm in Rhode Island, with no records whatsoever, I could only read the tombstones and surmise what might have happened. Some women died at early ages, probably associated with childbirth. This can often be confirmed by a birth date recorded on a nearby stone. A group of little mounds is in one corner of the cemetery, each marked by a small, unlabeled stone. These were probably stillborn infants or those who survived only briefly after birth. A better indication of health problems came from the finding that the only well on the farm was located about 30 feet downhill from the outhouse; only the hardiest ones survived.

    If a relative was in the military service during a war, he may well be buried in the military section of a cemetery. Following up on military service records and pension applications can be rewarding, especially if the veteran was wounded or became ill while on active duty. Military service records and subsequent pension applications on my great-grandfather, who served in the Civil War, produced 36 pages of records, including those of several complete physical examinations during service and subsequent descriptions supporting requests for an increased pension.

    Obituaries can be helpful if they give evidence that someone died at an early age of heart disease. Or they may mention death from leukemia or cancer, and even better, suggest donations to a specific disease-related charity. They also can contain valuable information about the names and whereabouts of surviving relatives.

    Hospital and medical records are well protected by laws, but may be accessed by the next of kin. Look also at where the relative was hospitalized during his or her lifetime; presence in mental hospitals could indicate schizophrenia or manic-depressive (now bipolar) illness, Hutchinson disease or some other heritable disorder. Was the person ever a patient in a neurological ward? Large city hospitals also serve a large population of patients suffering from alcoholism and chronic liver disease, but they also must care for many patients with terminal illnesses of all types.

    If there were surgical procedures performed, there will be records of the surgical diagnoses and even microscopic slides and tissue blocks which have been retained for many years. Also, most large hospitals have resident training programs and needed to maintain a high rate of autopsies on deceased patients to keep their certification as teaching hospital. Autopsy records are generally overlooked as sources of medical genealogical information but can provide the best possible information, as they not only include the pathologic findings but include a history of the clinical course of the disease. Autopsies performed by medical examiners for medical-legal purposes are usually very complete and detailed, but will lack the supporting clinical data.

    Most genetic diseases are still not diagnosed by genetic testing, nor will they be in the near future, because of the effort and expense involved. Even more important, the DNA test is probably not covered by health insurance. But almost every heritable disease has physical findings, X-ray patterns or several laboratory tests which are used for screening for the disease, plus others which help to confirm or establish the severity or the disease or monitor the effectiveness of treatment. If you can find the results, ask a physician to interpret them for you and you may have all the information you need. Other valuable data may also be available from CAT-scans, MRI, bone marrow studies, surgical pathology reports, ultrasound or other ancillary procedures. If cervical or uterine cancer is suspected, see if there are reports of suspicious or “Pap smears,” or cytopathology reports. Cytopathology studies are also done for lung cancer and to study suspicious fluids within the body.

    Prenatal diagnosis has long been possible for lipidoses, disorders of carbohydrate metabolism, mucopolysaccharidoses, and conditions involving amino acids. (Ref. Table 2 )

    Genetic testing is now available from chorionic biopsies or analysis of amniotic fluid during pregnancy; in some cases, positive findings are followed by interruption of the pregnancy. Very often these are done because there is a suspicion of a serious inherited disorder, such as Down syndrome, and there probably is a history of one of these diseases affecting related infants or children. These procedures are not without risk, and it is possible for in-utero death to occur to a normal fetus.

    If a family member underwent genetic testing as a part of a genealogical study, he or she no doubt signed an informed consent which prohibits release of medical data obtained without the consent of the subject. The banked DNA and the specific results on the subject’s sample remain the property of the subject from whom the sample was obtained. At this time, confidentiality regulations are not federally mandated but vary from

    Table 2. Some Possible Prental Tests

    Amino Acid and Related Disorders
    Arginosuccinic aciduria, citrullinemia, cystinosis, histidinemia, homocystinuria, maple syrup urine disease, methylmalonic aciduria

    Carbohydrate Metabolism Disorders
    Galactosemia, glucose-6-phosphate dehydrogenase deficiency (G6PD), glycogen storage diseases, mannosidosis

    Cholesterol ester storage disease, Fabry disease, Gaucher disease, globoid cell leukodystrophy, metachromatic leukodystrophy, Neimann-Pick disease, Refsum syndrome, Tay-Sach disease, Wolman syndrome

    Beta-glucuronidase deficiency, Hunter syndrome, Hurler syndrome, Sanfilippo syndrome, Scheie syndrome

    Other Disorders
    Adenosine deaminase deficiency, Down syndrome, familial hypercholesterolemia, hypophosphatemia, I-cell disease, Lesch-Nyhan syndrome, lysomal acid phosphatase deficiency, orotic aciduria, sickle-cell diseases and trait, testicular feminization, thalassemia, xeroderma pigmentosa

    Table 3. Detecting Common Heritable Diseases Without DNA Analysis

    Disorder Physical Findings, Tests
    Adenomatous polyposis of colon Blood in stools; colonoscopy, X-ray exams.
    Sigmoidoscopy or (preferably) colonoscopy
    Alcaptonuria Degenerative arthritis, pigmented cartilage; X-ray interveretebral disks.
    Urine: homogentisic acid increased
    Amino acid metabolic disorders Increased levels of amino acids or metabolic products in plasma, and/or urine
    Cystinosis Dwarfism, corneal opacities, rickets, uremia; cystine crystals in leukocytes
    Diabetes, type 2 Elevated glucose tolerance test
    Familial hypercholesterolemia Xanthomas, high serum cholesterol, check HDL/LDL ratio
    Gaucher disease Gaucher cells in bone marrow, lymph nodes, liver, spleen and other organs
    Gilbert syndrome (liver dysfunction) Elevated serum bilirubin
    Hemorrhagic telangiectasia Nosebleeds, GI bleeding, telangiectasis of tongue, lips, conjunctiva, ears, fingers; X-rays of lungs
    Hemochromatosis Check serum iron, iron-binding capacity, transferrin saturation, ferritin concentration
    Hemophilia A Bleeding history; factor VIII deficiency
    Hemophilia B Bleeding history; factor IX deficiency
    Huntington disease Personality changes, paranoia, dementia, choreic movements of extremities
    Maple syrup urine disease Progressive CNS deterioration after birth, maple syrup odor to urine & sweat; ketoacids in urine
    Marfan syndrome Elongated extremities, ectopic lens, heart murmurs; X-rays of hands
    Medullary carcinoma, thyroid Calcitonin plasma level
    Multiple endocrine adenomatosis (MEN-II syndrome) Ultrasound or scan of thyroid, calcitonin elevated, RIA assay of parathyroid hormone, MRI of abdomen, thyroid biopsy
    Myotonic dystrophy Muscular wasting, cataracts, frontal baldness, hypogonadism; slit-lamp exam, electromyography, immunoglobulins, EKG
    Nail-patella syndrome Absent patellas, dysplastic nails
    Neurofibromatosis Multiple peripehral neurofibromas, scoliosis, cafe aux lait spots on skin
    Ostogenesis imperfecta Multiple fractures, deafness, blue scleras; bone X-rays diagnostic
    Peutz-Jegher syndrome Pigmented spots on lips; X-ray small intestine
    Platelet disorders Platelet count in peripheral blood; bone marrow analysis
    Polycystic kidney disease Intravenous pyelogram, blood pressure, urinalysis
    Porphyria Urinary porphyrins, delta-aminolevulinic acid
    Sickle cell anemias Newborn screening by electrophoresis, chromatography or isoelectric focusing; metabisulfite slide preparations
    Spherocytosis Blood smear, reticulocyte count, osmotic fragility test
    Thromophilia Factor V Leiden coagulation screening test; activated protein C resistance
    Tuberous sclerosis Sebaceous skin lesions, white skin macules


    Table 1 Ethnic Predisposition for Heritable Disorders

    Note: The following data does not represent a uniform evaluation of risk factors for heritability, because it represents the experience and conclusions of multiple individuals and organizations. Also, for various reasons certain ethnic groups have been studied far more thoroughly than others. In some cases this may only indicate that the study best served the objectives of genomics companies or foundations anxious to make commercial or other use of the information.

    African Blacks, African Americans

      Birth defects: higher rate than Hispanics, Whites
      Breast cancer (most common cancer in African American women; high mortality rate, poorly differented type more common)
      Endometrial cancer: high incidence Esophagus: high cancer rate in Africa -- 15/100,000
      Gastric cancer: low rate
      G6PD deficiency common
      Hemoglobinopathies (including Hb S, Hb SC, Hb S-thalassemia, alpha and beta thalassemia) 1/600 carriers 1/12
      Kidney and renal pelvic cancer: 10-13/100,000 (men), 6 /100,000 (women)
      Possible genetic roles in incidence and severity of lupus erythematosus
      Liver and intraheptatic bile duct cancer: high rate
      Nasopharyneal cancer: 1/100,000 (males)
      Non-Hodkgin’s lymphoma: high rate
      Oral cavity (multiple cancers): highest rates
      Pancreatic cancer: high rates in males and females, 60% higher than Caucasians
      Prostate cancer rate high
      Thryroid cancer: 3.3 /100,000 (women)
      Uterine cervix cancer: fourth highest highest incidence

    Alaskan native

      Colonic and rectal cancer: high rate (4 X American Indians)
      Gastric cancer: high rate
      Lung and bronchial cancer: 71-89/100,000 (Native Alaskan males), 51/100,000 (Native Alaskan females)
      Uterine cervical cancer -- 15/100,000 in Native Alaskan women


      Auto-immune thyroid antibodies increased Polycystic ovarian disease


      Familial Mediterranean fever

    Ashkenazi Jews
    (Extensive research has been done on this population, as seen by the accompanying list. This does NOT mean that the incidence is significantly high in all of these conditions, but only that data is available for review if appropriate.)

    Disease Carriers
    Alpha thalassemia  
    Bloom syndrome unknown Carrier rate 1/110
    Breast cancers, BRCA-1, BRCA-2)  
    Canavan disease 1/6,000 Carrier rate 1/35-40
    Crohn’s disease High rate
    Colon cancer  
    Cystic fibrosis 1/3,200 Carrier rate 1/25
    Fabry disease  
    Familial Mediterranean fever  
    Familial dysautonomia 1/3800 Carrier rate 1/30
    Fanconi anemia unknown Carrier rate 1/89
    Gaucher disease 1/1,000 Carrier rate 1/10
    Machado Joseph disease  
    Multiple sclerosis 50-120/100,000
    Neimann-Pick disease 1/40,000 Carrier rate 1/70
    Parkinson disease  
    Tay-Sachs disease 1/2,500 to 1/3,600 Carrier rate 1/26 to 1/30
    Torsion dystonia 1/2,000 to 1/6,000
    Ulcerative colitis High rate

    Asians (see also S.E. Asians, Chinese)

      Alpha-thalassemia 1,2500 Carrier rate 1/25
      Behnet’s disease
      High incidence (18-20 percent) of genetic alleles causing poor
      metabolism of omeprazol, a drug used to treat peptic ulcer
      Kidney and renal pelvic cancer: very low rate
      Pancreatic cancer: low rate


      Malignant melanoma
      Kidney and renal pelvis: high incidence of cancer


      Alzheimer disease (early onset) in families
      Breast cancer
      Multiple sclerosis 50/100,000 but 344,1000 in Orkney, Shetland Islands
      Pernicious anemia

    Canada (see also French Canadians)

      Kidney and renal pelvic cancer: high incidence
      Multiple sclerosis 50-120/100,000

    Caucasians (see also by nationality, ethnic subgroups)

      Alzheimer disease
      Breast cancer (most common cancer in U.S. women)
      Colonic and rectal cancer: 4th most common, 2nd in causing death
      Cystic fibrosis (especially Northern Europeans)
      Endometrial cancer: high incidence
      Esophageal cancer: 5.3 - 5.6/100,000 (increased by alcohol, smoking)
      Gastric cancer: low rate
      Hereditary hemochromatosis
      Kidney and renal pelvic cancer: 10-13/100,000 (males), 6/100,000 (women)
      Melanoma -- incidence higher in fair-skinned people with blond or red hair, especially who freckle or sunburn easily
      Multiple sclerosis: 50-120/100,000
      Non-Hodgkin’s lymphoma 19.1/100,000 (males), 12.0/100,000 (females)
      Tay-Sachs Carrier rate 1/300
      Nasopharyngeal cancer: 1/100,000 (males and females)
      Oral cavity: Second highest rates (rate in males 2-4 times females)
      Urinary bladder cancer: 33.1/100,000 (Smoking, occupation increase rate)


      Alpha thalassemia 1/2,500 Carrier rate 1/25
      Behcet’s disease
      Cardiac arrhythmias (Wolff-Parkinson-White syndrome) high incidence
      Colonic and rectal cancer: high rate
      Esophageal cancer: 5.3 to 5.6 /100,000 men
      Gastric cancer: intermediate rate
      G6PD deficiency
      Kidney and renal pelvic cancer: low rate
      Lactase deficiency
      Liver and intrahepatic bile duct cancer: high rate Lung and bronchial cancer: 42-53/1000,000 (males),16-25/100,000 (females Nasopharyngeal cancer: 10.8/100,000 (males)
      Ovarian cancer: lowest rate
      Pancreatic cancer: low rate


      Adrenogenital syndrome
      Pseudocholinesterase deficiency (can cause complications associated with anesthesia)


      Esophageal cancer: lowest rate -- 2.9/100,000
      Gastric cancer: low rate
      Kidney and renal pelvic cancer: low rate
      Lung and bronchial cancer: 42-53/100,000 (males), 16-25/100,000 (females)
      Nasopharyngeal cancer: 3.9/100,000 (males)
      Thyroid cancer: high rate 14.6/100,000 (females), 4.1/100,000 (males)


      Aberrant gene for type 2 diabetes
      Congenital nephrosis
      Hereditary non-polyposis colorectal carcinoma
      Platelet glycoprotein abnormality -- early onset cardiac death

    French Canadians



      Beta-thalassemia 1/3,600 Carrier rate 1/30


      Colonic cancer: high incidence and mortality rates
      Endometrial cancer: highest incidence in world, plus high mortality rate
      Gastric cancer: high rate
      Pancreatic cancer: rate exceeds that of Caucasians
      Thyroid cancer: high (women)

    Hispanics, Mexican-Americans (Heterogeneous group)

      Birth defects: lower rate than whites
      Type 2 diabetes mellitus: high rate
      Esophageal cancer: under 5.3/100,000 for men
      Gastric cancer: intermediate rate
      Hypothyroidism -- more common than in African Americans
      Kidney and renal pelvic cancer: 10-13/100,000 (males), 6/100,000 (women)
      Lung and bronchial cancer: 42-53/100,000 (males), 15-25/100,000 (females)
      Nasopharyngeal cancer: 1/100,000 (males)
      Non-Hodgkin’s lymphoma: 3rd highest rate (males)
      Pancreatic cancer: low rate
      Uterine cervical cancer -- 15/100,000 (third highest incidence) Hutterite population (U.S.)
      Genetic correlation with low density lipoproteins, fat-free mass, systolic blood pressure


      Punjab population -- morphological traits Iran
      Behçet’s disease Iraq
      Immunologlobulin levels higher in Kurds than Arabs, but also strong environmental correlation


      Beta-thalassemia 1,3,600 Carrier rate 1/30


      Pernicious anemia


      Autosomal recessive juvenile Parkinonism
      Colonic and rectal cancer: second highest rate in U.S. (mostly males)
      Esophagus -- 5.3-5.6/100,000
      Gastric cancer: high (not in 2nd generation Japanese Americans)
      Uterine cervical cancer: low rate in Japanese women (5.8/100,000)
      Lung and bronchial cancer: 42-53/100,000 (Japanese American males), 15/100,000 (Japanese American females)
      Ovarian cancer: high rate
      Thyroid cancer: rate low (males) 1.6/100,000


      Breast cancer (low rate in Korean women)
      Behçet’s disease -- 13.5-20/1,000
      Lung and bronchial cancer: 53/100,000 (males)
      Non-Hodgkin’s lymphoma: 5.8/100,000 (males), 6.0/100,000 (females)
      Uterine cervical cancer -- 15/100,,000 in Korean women (second highest rate)
      Ovarian cancer: lowest rate Kurds
      Immunoglobulin levels in Iraq’s Kurds higher than Iraq’s Arabs Lebanese
      Homozygous familial hypercholesterolemia Mediterranean ethnic groups (Italian, Greek, Sephardic Jews)
      Beta Thalassemia
      Familial Mediteranean fever
      G6PD deficiency
      Glycogen storage disease type III


      Positive genetic correlation, thyroxine

    Native Americans

      Breast cancer: low rate in Native American women
      Beta globulin gene variants
      Colonic and rectal cancer: low incidence
      Diabetes mellitus type 2
      Kidney and renal pelvic cancer: highest rate (males)
      Ovarian cancer: highest rate

    New Zealand

      Kidney and renal pelvic cancer: high incidence
      Multiple sclerosis 50-120/100,000

    Northern Europeans

      Cystic fibrosis
      Kidney and renal pelvic cancer: high incidence
      Multiple sclerosis 50-120/100,000

    Pacific Island Populations

      Throid cancer: high incidence


      Physical malformations (attributed to cosanguiity)


      Caucasus -- pos. psychophysiological traits, PTC sensitivity
      Genetic ischemic heart disase higher in Russian males (15.1 percent) than in Uzbek males (10.7 percent)
      Multiple sclerosis 50-120/100,000 Scandinavians
      Pernicious anemia South Africans (White)
      Porphyria variegata

    Southeast Asians

      Behçet’s disease 13.5-20 cases/1,000
      Alpha-thalassemia: high rate
      Behçet’s disease: high rate
      Gastric cancer: high rate
      Multiple sclerosis 50-120/100,000
      Thyroid cancer

    Saudi Arabia

      Behçet’s disease 13.5-20 cases/100,000

    Thailand (see Southeast Asians)

      Kidney and renal pelvic cancer: low rate
      Liver and intraheptic bile duct cancer: high rate


      Behçet’s disease 80-370/100,000


      Large familial group with Huntington disease


      Gastric cancer: high in males (1.6 times Japanese)
      Liver and intraheptic bile duct cancer: high rate -- 41.8/100,000 in males
      Nasopharyngeal cancer: 7.7/100,000 (males)
      Non-Hodgkin’s lymphoma: 2nd highest rate (males)
      Oral cavity (multiple cancers): 2nd highest rates (males)
      Thyroid cancer: high 10.5/100,000 (women)
      Uterine cervial cancer: highest rate in Vietnamese women -- 43/100,000

    Note: This represents a sampling of some of the studies that have been done to see which ethnic groups are at risk for certain diseases. If you are concerned about a condition that is not mentioned above, look up the disease or health problem on the internet. Nearly all diseases now have several websites and one or more foundations interested in disseminating knowledge about the condition and raising money for research to improve diagnosis and treatment. The National Institutes of Health not only provide statistics on the incidence of some diseases in both males and females of various ethnic groups but also data on the severity of those diseases, which can vary greatly from one ethnic group to another. Also it should be recognized that all ethnic groups have varying degrees of heterogenicity -- that is, there was cross-breeding with other groups in the past. And the environment plays an enormous role in many of the diseases, so that a person of one nationality may have a far different susceptibility to a certain disease if that person has emigrated to somewhere else in the world.

    Figure 1.Pedigree Pattern of an Autosomal Dominant Trait

    There is a vertical pattern of inheritance. Affected males are solid squares, affected females are solid circles; unaffected males are open squares, unaffected females are open circles.

    Examples: Acute porphyria, angioedema (hereditary), Bloom syndrome, hemochromatosis, hemorrhagic telangiectasis (hereditary), Huntington disease, hypercholesterolemia (familial), leukemia in Down syndrome), Marfan sydrome, multiple congenital plyposis of colon, nail-patella syndrome, nephritis (hereditary), neurofibromatosis, osteogenesis imperfecta (l type), Peutz-Jegher’s syndrome, polycystic disease (adult), Tourette syndrome, tuberous sclerosis, Von Willibrand’s disease, Wiskott-Aldrich syndrome, Wolff-Parkinson-White syndrome.

    Figure 2. Pedigree Pattern of an Autosomal Recessive Trait

    There is a horizontal inheritance pattern. Affected males are solid squares, affected females are solid circles; unaffected males are open squares, unaffected females are open circles. = is cosanguinous mating

    Examples: albinism, beta-thalassemia, deafness, cystic fibrosis, Hurler syndrome, Mediterranean fever (familial), phenylketonuria, progressive myoclonial epilepsy (familial), sickle-cell trait, Wilson’s disease

    Figure 3. Pedigree Pattern of an X-Linked Dominant Trait

    Affected hemizygous males are solid squares; affected heterozygous females are solid circles. Unaffected males are open squares, unaffected females are open circles.

    Figures 4A-C Pedigree Patterns, X-Linked Recessive Trait

    These show an oblique pattern of inheritance.

    1. (top) An unaffected male mates a carrier female. Affected males are black squares, affected females are black circles. Carrier females have a central dot. Unaffected males are hollow squares, unaffected females are hollow circles.
    2. (middle) A cosanguinous marriage
    3. (bottom) An affected male mating a carrier female has all normal sons, all carrier daughters.

      Examples of X-linked disorders: agammaglobulinemia (sex-linked), Christmas disease (Factor IX deficiency), color blindness, Fabry’s disease, glucose 6-phosphate dehydrogenase deficiency, hemophilia A, leukodystrophies (some sex-linked)

    Figure 5. Abbreviated Pedigree of Large Kindred: 5 Subfamilies over 7 Generations and 394 Known Descendants of Generation 1

    Newman, John H. et al. N Engl J Med 2002; 345: 320-1

    The propositus (arrow), was a woman in generation V of Subfamily 14 who died at age 30. At least 200 descendants have varying degrees of risk for primary pulmonary hypertension. The familial form of the disease was diagnosed in 16 women and 2 men; 20 of 23 other known carriers are shown in the chart. Unaffected members are open symbols; those with pulmonary hyptertension are solid symbols; carriers are symbols with dots. Males are squares, females circles, slashes represent deceased family members. Numbers within the circles indicate the totals of that sex. Numbers beneath symbols indicate ages.







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