Last year I attended a presentation by Dr. Ohad Birk of Ben Gurion University about the value of genetic testing in the desert Bedouin people in Israel. Apparently the Bedouins have a high rate of close inter-marriage resulting in mutations matching up in the offspring leading to devastating rare genetic diseases. Obviously this carried a heavy emotional price. Since Bedouins are Israeli citizens and entitled to universal health care, this also carries increased health care costs for the taxpayers. Dr Birk explained how his program of testing and counseling saves tens of millions of dollars by preventing these genetic diseases.(11)(12)(13)

Image at Right: Bedouin Woman in Jerusalem 1898 Courtesy of the United States Library of Congress's Prints and Photographs Division

It is amazing to think about it, but a number of online DNA testing companies offer the same testing services provided by Dr. Ohad Birk: DNA Direct,  23andMe, DeCodeMe, Navigenics,  Knome, and MDL.

DNA Direct is one of these online genetic testing services offering a reasonable list of tests. Each test actually corresponds with a known risk for disease or clinical abnormality.(7)  Before you go online for your testing, however, you might want to discuss this with your doctor who can order the same genetic test through Quest or LabCorp at your next routine blood draw. 

If Anonymity is an Issue

Rather than going through their doctor, many people choose anonymous online genetic testing  in order to maintain confidentiality of test results from the insurance companies. A positive result may have a negative impact on future health insurability, etc.

The senate passed an anti-discrimination bill April 2008 to prevent health insurance companies from canceling coverage based on results of genetic testing. However, I remain skeptical, and doubtful that this offers any real protection.

Beware that many of the genetic tests offered online are not ready for clinical use, and may be premature.  However, DNA Direct has a reasonable list which are described below.  This is a rapidly  evolving field.
  
List of Online Tests Offered by DNA Direct:(7)

Alpha-1 Antitrypsin Deficiency, Asthma and Lung Disease

Alpha-1 Antitrypsin is a protein in the lung tissue, and deficiency leads to a tissue breakdown in the lung causing pulmonary emphysema.(1) 

Alpha-1 Carrier Status

About 1 in every 10-30  Americans are Alpha-1 carriers. While carriers are usually asymptomatic,  they may be more susceptible to lung injury from toxins such as cigarette smoke, or susceptible to liver injury from toxins such as acetaminophen (tylenol).  Preventive measures include avoidance of lung and liver toxins.  Most Alpha-1 carriers have enough protein production to remain disease free.

Image at left: structure of alpha-1-anti-trypsin protein courtesy of wikipedia.

Severe Alpha-1 Deficiency

An estimated 100,000 people in the U.S. (1 in 2500) and a similar number in Europe have severe Alpha-1 antitrypsin deficiency.  Since the symptoms of asthma are common in the general population, Alpha-1 patients are most often misdiagnosed as having asthma.   On average it takes seven years and three doctors to make the correct diagnosis of alpha-1 which causes 3 percent of all cases of emphysema, and COPD (chronic obstructive pulmonary diseases) in the U.S. 

There is a treatment with Prolastin (Bayer), which is purified alpha-1-anti-trypsin protein,  is available.(8)  If the patient has asthma, it might be reasonable to test for Alpha-1 in order to make the diagnosis. 


Ancestry and Ethnicity Test Panel 

Ashkenazi Jewish Carrier Screening Panel (in Alphabetical Order)

Left Image: Ahkenazi Shofar Courtesy of Wikipedia.

Bloom Syndrome: The carrier frequency in individuals of Eastern European ancestry is about 1/100. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child.

Bloom syndrome is caused by mutations in the BLM gene responsible for the DNA helicase, an enzyme that unwinds the two spiral strands of a DNA molecule so that they can be copied.  The chromosome copying mechanism is faulty causing a high risk for early cancer in affected individuals.

Canavan Disease: One in 40 individuals of Ashkenazi Jewish ancestry is a carrier of Canavan disease. 

Canavan disease is a leukodystrophies, characterized by degeneration of myelin, which is the fatty covering that insulates nerve fibers in the brain causing abnormal neurological development, and poor survival of the affected child.  The American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology (ACOG) recommend Canavan carrier screening for all Ashkenazi Jewish individuals.

Cystic Fibrosis: One in 25 Ashkenazi Jewish individuals are CF carriers. The American College of Obstetrics and Gynecology (ACOG) recommends that all couples who are pregnant or planning a pregnancy be offered CF carrier screening.

Familial Dysautonomia: Autosomal recessive, and almost exclusively in Ashkenazi Jews.  Both parents must be carriers in order for the child to be affected. The carrier frequency in Jewish individuals of Eastern European (Ashkenazi) ancestry is about 1/30, while the carrier frequency in non-Jewish individuals is about 1/3000. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child.  Genetic counseling and genetic testing is recommended for families who may be carriers of familial dysautonomia.(2)

Fanconi Anemia: One in 89 Ashkenazi Jewish individuals is a carrier of Fanconi anemia Type C.

Gaucher Disease: About 1 in 100 people in the U.S. population are carriers, and about 1 in 15 Ashkenazi Jews are carriers for Gaucher's disease. 

Gaucher's disease is the most common of the storage diseases caused by a deficiency of the lysosomal enzyme glucocerebrosidase, which breaks down glucocebrosides, found in red and white blood cell membranes. This leads to an accumulation a fatty substance in various RE and filtering organs such as the spleen, liver, kidneys, lungs, as well as brain and bone marrow.  Symptoms may include hepatosplenomegaly, skeletal disorders and severe neurologic abnormalities.

There is an effective  treatment with enzyme replacement with recombinant glucocerebrosidase given intravenously every two weeks which can dramatically reverse the symptoms.  However, this treatment with Cerezyme costs $500,000 annually for the lifetime of the patient.

Mucolipidosis IV: About 1 in 100 Ashkenazi Jewish individuals is a carrier. Mucolipidosis is a neurodegenerative lysosomal storage disorder.  Symptoms include agenesis of the corpus callosum, neurological and opthalmic abnormalities.

Niemann-Pick Disease: Caused by the deficiency of the enzyme, acid sphingomyelinase, leading to accumulation of sphingomyelin in the liver and spleen (hepatosplenomegaly), progressive deterioration of the nervous system, and poor survival in the severe form of the genetic disease.  One in 90 people with Ashkenazi Jewish ancestry is a carrier of Niemann-Pick Type A (severe) or Type B (less severe form).(3)

Tay-Sachs Disease: One in 30 people with Ashkenazi Jewish ancestry is a carrier of Tay-Sachs disease. Because of the high carrier rate, the American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology (ACOG) recommend screening for Ashkenazi Jewish individuals. ACOG recommends that couples in which only one member is Ashkenazi Jewish also consider carrier testing for Tay-Sachs disease.

Tay-Sachs disease is a severe progressive disorder that causes deterioration of the central nervous system, resulting in poor muscle tone, loss of motor skills, seizures, blindness, and difficulties with swallowing and breathing. On eye exam, people with Tay-Sachs disease have an unusual appearance to the retina, known as a cherry-red spot. Children born with Tay-Sachs disease appear normal at birth, however symptoms begin as early as 3 months of age and death usually occurs by age 4. There is no cure for Tay-Sachs disease.

Blood Clotting Disorders (Factor V Leiden, Prothrombin)

This genetic test looks for a mutation in two genes which increase risk for blood clots, factor V Leiden, and prothrombin mutation.  These lead to increase risk for deep venous thrombosis in the calf veins, and associated pulmonary embolism.  Once identified as a carrier, one can take precautions to prevent deep venous thrombosis.

Factor V Leiden

Factor V Leiden is found in 1 in 20 Caucasians, and is rare in Hispanic Americans, and African Americans.  A mutation here increases the risk of blood clot formation.

Factor V Leiden is also found in 10% to 20% of people of all ages with first-time venous blood clots, 40% of people younger than 50 with first-time venous clots, and 60% of pregnant women with venous thrombosis.

Factor V Leiden has been associated with an increased risk of recurrent pregnancy loss, severe  preëclampsia, fetal growth retardation, stillbirth, and placental problems (infarction and abruption).

Prothrombin (Factor II) G2021A

Similar to Factor V Leiden, the Prothrombin mutation is found in about 1% to 2% of the Caucasian population. It is rare in the African and Asian populations.  Prothrombin G2021A is found in 6% to 8% of people with a first-time venous clot, has been associated with myocardial infarction (heart attack) in young women and cerebral (brain) venous thrombosis. 


Breast & Ovarian Cancer Risk-BRCA1 and BRCA2

Hereditary cancer has general features that include: Cancer diagnosed at a young age (earlier than 50 years old), multiple primary cancers in the same person, a combination of certain cancers in a family, such as breast and ovarian or colon and uterine.

Key features in history suggesting hereditary breast and ovarian cancer are:

1) Breast cancer before age 50
2) Ovarian cancer at any age
3) Breast cancer in both breasts
4) Breast cancer and ovarian cancer in the same person.
5) Male breast cancer
6) Ashkenazi Jewish ancestry 

Genetic testing for breast and ovarian cancer deals with two extremely large genes — called BRCA1 and BRCA2 — and hundreds of possible mutations.

Ashkenazi Jews, however, present a simplified pattern, mostly involving one of three specific BRCA mutations. This test, called multisite analysis, looks exclusively for three mutations in the BRCA1 and BRCA2.

Colon Cancer Screening. The DNA Stool Test  examines a stool sample for 23 DNA markers that are associated with colorectal cancer and pre-cancerous polyps.

Cystic Fibrosis- CFTR gene.

Cystic fibrosis (CF) is a disease of thick mucous affecting lungs, liver, and pancreas, charaterized by repeatd and frequent lung infections, digestive problems with decreased pancreatic enzyme production.  These in turn cause growth retardation and deficiency in fat-soluble vitamins A, D, and E.  The diagnosis of CF can be made with sweat test.  There is no cure for CF.  Life expectancy is shortened with most succumbing to lung infection in their 20s and 30s. CF is a common genetic disorder with  5% of people of European descent carriers for CF with one gene affected.

Above Image: Cystic fibrosis breathing treatment courtesy of Wikipedia

CF is caused by a mutation in CFTR gene, making an abnormal chloride ion channel which makes sweat, digestive juices, and mucus. Professional medical groups including the NIH, ACUG, and ACOG recommend that CF carrier screening be offered to all couples who are planning a pregnancy or are currently pregnant.

Drug Response Testing

Three genes are responsible for enzymes that metabolize medications.  Mutations in these genes can produce '"poor metabolizers" who nee lower doses of medication to avoid overdose.  This information is useful in personalizing drug treatment.

Hemochromatosis

Hemochromatosis (iron accumulation) is the most common genetic disorder in Caucasians, with an estimated prevalence of 1/4 to 1/2 per cent having both genes affected (homozygotes) and 10-12 per cent carriers (one gene).

Iron accumulation of heochromatosis is an example of a common genetic disorder whiich has a curative treatment if diagnosed early.  This treatment is bleeding or phlebotomy which removes the iron from the body. Those 18th century bleeding treatments weren't so ridiculous after all.  

The disease causes iron accumulation in the liver, adrenals, heart and pancreas, causing cirrhosis, adrenal insufficiency, heart failure and diabetes. The cirrhosis is associated with increased risk of liver cancer.  The more common clinical presentations are malaise, liver cirrhosis, insulin resistance, diabetes mellitus type 2 (due to pancreatic damage), erectile dysfunction, decreased libido, congestive heart failure, arrhythmias, arthritis, adrenal insufficiency, deafness, parkinsonian symptoms, hypothyroidism, a darkish colour to the skin (Diabetes bronze), etc.
 
Males are usually diagnosed after their forties and fifties, and women several decade later owing to regular iron loss through menstruation (which ceases in menopause). Many patients who have the full blown genetic mutation (homozygous) may be asymptomatic, or have minimal symptoms, showing only an elevated ferritin or saturation.  Diagnosis is commonly made with elevated LFT's (liver enzymes), elevated ferritin, and increased iron binding saturation. DNA testing for two mutations in the HFE gene, C282Y and H63D, makes the diagnosis (available at Quest and Labcorp). (9)(10)

Imaging features: The increased iron stores in the liver and pancreas result in characteristic findings on unenhanced CT and a decreased signal intensity at MR imaging. 

Routine screening of population for haemochromatosis is generally not done, since serum ferritin is a more practical and less expensive marker. Serum ferritin above 1000 ng/mL suggests iron overload.

Left image: ferritin protein structure courtesy of wikipedia
 
Early diagnosis allows prompt curative treatment with phlebotomy (discarded blood donation) which removes iron from the body.  Treatment is usually started with ferritin above 200-300 mg/L.

Warfarin Response Testing

Warfarin response testing looks at two genes, called CYP2C9 and VKORC1 which determine our response to coumadin.  CYP2C9 is a gene involved in warfarin metabolism.  CYP2C9 variants have reduced metabolism and generally require lower warfarin doses. VKORC1 is involved in vitamin K epoxide reductase, or VKOR which makes the blood-clotting proteins.  Warfarin works by reducing this enzyme's activity.  A common VKORC1 gene variant (called -1639G>A) also reduces the enzyme’s activity.  If one has  low enzyme levels to start with, an average warfarin dose may be too much, and cause excessive bleeding.

Above image:CYP2C9 protein courtesy of wikipedia

Cardiovascular Disease

 

The most common inherited cardiovascular diseases which have genetic testing are:

Hypertrophic cardiomyopathy (HCM) is most common affecting 0.1 per cent of the population.  It causes muscle thickening in the ventricles of the heart.  Many are asymptomatic, however, symptoms may include shortness of breath, tiredness, chest pain, fainting or near-fainting, or heart palpitations.

Dilated Cardiomyopathy (DCM): This causes the heart to enlarge, weaken, and reduce pumping ability causing heart failure, fatigue, shortness of breath, and fluid retention with swelling of the ankles and feet.

Inherited Arrhythmias are abnormal heart beats or rhythms caused by gene mutations causing  faintness, dizziness, and heart palpitations.

Marfan Syndrome is a genetic disorder of the connective tissue involving the eyes, skin, bone, and heart producing sympoms such as nearsightedness or arrhythmias.
 
Familial Aortic Aneurysm (FAA) causes the aorta starts to stretch and bulge called an aneurysm. The aorta is a large blood vessel that carries blood from the heart to the rest of the body. Symptoms may include general abdominal pain or discomfort, or pain in the chest or lower back.

Coronary Artery Disease - Heart Disease

See this article: http://www.genetichealth.com/HD_Genetics_of_Coronary_Artery_Disease.shtml
Genetics of Heart Disease - Inheritance Patterns - Review Article

So far, there are 250 genes involved in heart disease producing a blended effect.  This makes things complicated. A person may have some mutations that increase risk and other mutations  decrease risk. On average, a person's risk level is approximately midway between those of the parents.

LDL Metabolism,  LDL Receptor. 1985, Michael Brown and Joseph Goldstein  Nobel prize for gene for familial hypercholesterolemia, or FH.  FH is inherited in a dominant manner. 

Apolipoprotein E.  More than 30 mutant forms of apo E. the e4 version of the gene tend to have higher cholesterol levels than the general population, but levels in people with the e2 version are significantly lower. The apo E gene has also been implicated in Alzheimer's disease. 

Apolipoprotein(a). Apo(a) combines with LDL to form Lp(a) often found as a part of plaques . High Lp(a) levels (over 30 mg/dL) indicates higher risk of developing CAD. Lp(a) levels may be reduced with the vitamin niacin, or by hormone replacement therapy in postmenopausal women.
  
Homocysteine Metabolism, (hyperhomocystinemia) is known to be a risk factor for CAD.  In the US, about one in eight people have a mutation for MTHFR, with elevation in homocysteine, treatable with folate, B6 B12 vitamins.

Apolipoprotein A1 is a protein found in the HDL particle, the  "good cholesterol". Some mutations  in the apo A1 gene result are bad causing early heart attacks, and strokes. 

A particular mutation in Apo A1 found in some residents of Milan, Italy, called the "Milano" mutation results in very low levels of HDL. Although these people have very low levels of HDL, they also have a low incidence of Heart Disease.

Genetic Testing for CAH - Coronary Artery Disease

In general, tests for specific genetic mutations are not performed in CAD. Indirect tests are much easier and less expensive.  For example, blood homocysteine levels are useful.  If elevated, treatment is B6 B12 and folate vitamins.

Celiac Disease

EnteroLab offers a home test kit for both antibodies and genetic testing for celiac disease.  This is a test kit sent to the home, and a stool sample is provided and mailed back to the lab.  One of my patients had spent years going to multiple doctors with severe neurapathies and various other symptons of celiac disease and had been told all her tests were negative.  Her EnteroLab test was positive and she has improved dramatically on a gluten free diet.

For more information on celiac disease see my previous article:
All About Celiac Disease, and Gluten by Jeffrey Dach MD


Conclusion

In conclusion, whether or not to do genetic testing can be a complicated question.  Sometimes it is very useful, sometimes not.  Sometimes it may lead to difficult moral and ethical questions when applied to the unborn child. 

In some cases gene testing is useful for the individual to confirm a diagnosis, such as alpha 1 anti-trypsin deficiency in the asthmatic patient, or to confirm hemochromatosis in the patient with elevated ferritin. Gene testing may be useful to predict future disease risk, such as cancer risk with BRCA genes, so that preventive measures can be taken. 

Genetic testing may be useful for family planning.  When parents have knowledge of their carrier status, they can take precautions to prevent a severe a genetic disease in the unborn child.  Obviously there are ethical issues to be considered in regards to eugenics which we have not touched upon. This is the subject for a later report.

In some cases, genetic testing is either redundant or simply not useful.  For example, there is no reason to do genetic testing for type two diabetes when the fasting blood sugar is already abnormal and is a more useful marker.  There is no reason to do genetic testing for familial hypercholesterolemia when the routine lipid panel provides this information.  Likewise, there is no reason to do genetic testing to determine eye color or hair color when a simple examination provides this information.

Genetic testing a rapidly evolving field, and new information is coming online all the time.

Very soon, the cost for routine whole human genome sequencing will become cheaper, and some day will be offered during routine clinical testing along with the CBC, blood count and chemistry panel.  Also, we will very soon have a greater understanding of gene variation and disease risk, which will hopefully allow intelligent and useful interpretation of the routine clinical sequencing of the entire human genome.  As of May 2008, we are not quite there yet.

Jeffrey Dach MD

Financial Disclosure: I have no financial interests in any companies or products mentioned in this article.

References