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Background
According to the American College of Medical Genetics, an important issue in genetic testing is defining the scope of informed consent. The obligation to counsel and obtain consent is inherent in the clinician-patient and investigator-subject relationships. In the case of most genetic tests, the patient or subject should be informed that the test might yield information regarding a carrier or disease state that requires difficult choices regarding their current or future health, insurance coverage, career, marriage, or reproductive options. The objective of informed consent is to preserve the individual's right to decide whether to have a genetic test. This right includes the right of refusal should the individual decide the potential harm (stigmatization or undesired choices) outweighs the potential benefits.
DNA-based mutation analysis is not covered for routine carrier testing for the diagnosis of Tay-Sachs and Sandhoff disease. Under accepted guidelines, diagnosis is primarily accomplished through biochemical assessment of serum, leukocyte, or platelet hexosaminidase A and B levels. The literature states that mutation analysis is appropriate for individuals with persistently inconclusive enzyme-based results and to exclude pseudo-deficiency (non-disease related) mutations in carrier couples.
Testing of a member who is at substantial familial risk for being a heterozygote (carrier) for a particular detectable mutation that is recognized to be attributable to a specific genetic disorder is only covered for the purpose of prenatal counseling under plans with this benefit (see CPB 189 - Genetic Counseling).
Confirmation by molecular analysis of inborn errors of metabolism by traditional screening methodologies (e.g., Guthrie microbiologic assays) is covered. Rigorous clinical evaluation should precede diagnostic molecular testing.
In many instances, reliable mutation analysis requires accurate determination of specific allelic variations in a proband (affected individual in a family) before subsequent carrier testing in other at-risk family members can be accurately performed. Coverage of testing for individuals who are not Aetna members is not provided, except under the limited circumstances outlined in the policy section above.
Hereditary Non-Polyposis Colon Cancer
Hereditary non-polyposis colon cancer ([HNPCC], Lynch syndrome) is one of the most common cancer predisposition syndromes affecting 1 in 200 individuals and accounting for 13-15% of all colon cancer. HNPCC is defined clinically by early-onset colon carcinoma and by the presence of other cancers such as endometrial, gastric, urinary tract and ovarian found in at least three first-degree relatives. Two genes have been identified as being primary responsible for this syndrome: hMLH1 at chromosome band 3p21 accounts for 30% of HNPCC2,3 and hMLH2 or FCC at chromosome band 2p22 which together with hMLH1 accounts for 90% of HNPCC.
Unlike other genetic disorders that are easily diagnosed, the diagnosis of HNPCC relies on a very strongly positive family history of colon cancer. Specifically, several organizations have defined criteria that must be met to make the diagnosis of HNPCC.
The most widely accepted of these are the Amsterdam 1 criteria, which include:
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Three affected relatives; and
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Two generations affected; and
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One first or second degree relative affected before the age of 50.
All three criteria must be met to make a diagnosis of HNPCC.
According to guidelines from the American College of Medical Genetics, genetic testing for HNPCC may be indicated in patients who meet the Bethesda Criteria (Modified). The Bethesda Criteria (Modified) include:
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Amsterdam 1 Criteria-positive families; or
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Individuals with 2 HNPCC-related cancers including synchronous/metachronous colorectal cancers or extracolonic cancers (e.g., endometrial, ovarian, gastric, hepatobiliary, small bowel, and transitional cell); or
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Individuals with colorectal cancer and a 1st degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma (cancer less than 50 years old and adenoma less than 40 years old); or
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Colorectal or endometrial cancer less than 50 years old; or
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Right-sided colorectal cancer with undifferentiated pattern on pathology less than 50 years old; or
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Signet ring cell colorectal cancer less than 50 years old; or
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Colorectal adenoma less than 40 years old.
Genetic testing for HNPCC may be medically necessary for patients who meet any of these criteria. Although HNPCC lacks strict clinical distinctions that can be used to make the diagnosis, and therefore diagnosis is based on the strong family history, genetic testing is now available to study patient's DNA for mutations to one of the mismatch repair genes. A mutation to one of these genes is a characteristic feature and confirms the diagnosis of HNPCC. Identifying individuals with this disease and performing screening colonoscopies on affected persons may help reduce colon cancer mortality.
Microsatellite instability (MSI) is found in the colorectal cancer DNA (but not in the adjacent normal colorectal mucosa) of most individuals with germline mismatch repair gene mutations. In combination with immunohistochemistry for MSH2 and MLH1, MSI testing using the Bethesda markers should be performed on the tumor tissue of individuals putatively affected with HNPCC. A result of MSI-high in tumor DNA usually leads to consideration of germline testing for mutations in the MSH2 and MLH1 genes. Individuals with MSI-low or microsatellite stable (MSS) results are unlikely to harbor mismatch repair gene mutations, and further genetic testing is usually not pursued.
HNPCC is caused by germline mutation of the DNA mismatch repair genes. Over 95% of HNPCC patients have mutations in either MLH1 or MSH2. As a result, sequencing for mismatch repair gene mutations in suspected HNPCC families is usually limited to MLH1 and MSH2 and sometimes MSH6. In general, MSH6 sequence analysis is performed in persons meeting aforementioned criteria for genetic testing for HNPCC, and who do not have mutations in either the MLH1 or MSH2 genes. In addition, single site MSH6 testing may be appropriate for testing family members of persons with HNPCC with an identified MSH6 gene mutation.
HNPCC is a relatively rare disease, which makes screening the entire populace burdensome and not cost-effective. The incidence of this disease, even among the families of patients with colon cancer, is too small to make screening effective. (See also CPB 189 - Genetic Counseling and CPB 227 - BRCA Testing, Prophylactic Mastectomy, Tamoxifen, and Prophylactic Oophorectomy for Persons at Risk for Breast and Ovarian Cancer).
Familial adenomatous polyposis (FAP)
Familial adenomatous polyposis (FAP) is caused by mutation of the adenomatous polyposis coli (APC) gene. According to guidelines from the American Gastroenterological Association (AGA, 2001), adenomatous polyposis coli gene testing is indicated to confirm the diagnosis of familial adenomatous polyposis, provide presymptomatic testing for at-risk members (first degree relatives 10 years or older of an affected patient), confirm the diagnosis of attenuated familial adenomatous polyposis in those with more than 20 adenomas, and test those 10 years or older at risk for attenuated familial adenomatous polyposis.
AGA guidelines state that germline testing should first be performed on an affected member of the family to establish a detectable mutation in the pedigree. If a mutation is found in an affected family member, then genetic testing of at-risk members will provide true positive or negative results. AGA guidelines state that, if a pedigree mutation is not identified, further testing of at-risk relatives should be suspended because the gene test will not be conclusive: a negative result could be a false negative because testing is not capable of detecting a mutation even if present. When an affected family member is not available for evaluation, starting the test process with at-risk family members can provide only positive or inconclusive results. In this circumstance, a true negative test result for an at-risk individual can only be obtained if another at-risk family member tests positive for a mutation.
MYH-Associated Polyposis
MYH is a DNA repair gene that corrects DNA base pair mismatch errors in the genetic code before replication. Mutation of the MYH gene may result in colon cancer. In this regard, the MYH gene has been found to be significantly involved in colon cancer, both in cases where there is a clear family history of the disease, as well as in cases without any sign of a hereditary cause.
The National Comprehensive Cancer Network (NCCN)'s practice guidelines on colorectal cancer screening (2006) recommended testing for MYH mutations for individuals with personal history of adenomatous polyposis (more than 10 adenomas, or more than 15 cumulative adenomas in 10 years) either consistent with recessive inheritance or with adenomatous polyposis with negative adenomatous polyposis coli (APC) mutation testing. The guideline noted that when polyposis is present in a single person with negative family history, de novo APC mutation should be tested; if negative, testing for MYH should follow. When family history is positive only for a sibling, recessive inheritance should be considered and MYH testing should be done first. In a polyposis family with clear autosomal dominant inheritance, and absence of APC mutation, MYH testing is unlikely to be informative. Members in such family are treated according to the polyposis phenotype, including classical or attenuated FAP.
Factor V Leiden Mutation
Factor V Leiden mutation is the most common hereditary blood coagulation disorder in the United States. It is present in 5% of the Caucasian population and 1.2% of the African-American population. Factor V Leiden increases the risk of venous thrombosis 3-8 fold for heterozygous individuals and 30-140 fold for homozygous individuals. Factor V Leiden mutation has been associated with the following complications:
According to the American College of Medical Genetics, Factor V Leiden genetic testing is indicated in the following patients:
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Age less than 50, any venous thrombosis; or
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Venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins); or
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Recurrent venous thrombosis; or
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Venous thrombosis and a strong family history of thrombotic disease; or
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Venous thrombosis in pregnant women or women taking oral contraceptives; or
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Relatives of individuals with venous thrombosis under age 50; or
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Myocardial infarction in female smokers under age 50.
The ACMG does not recommend random screening of the general population for factor V Leiden. Routine testing is also not recommended for patients with a personal or family history of arterial thrombotic disorders (e.g., acute coronary syndromes or stroke) except for the special situation of myocardial infarction in young female smokers. According to the ACMG, testing may be worthwhile for young patients (less than 50 years of age) who develop acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease. The ACMG does not recommend prenatal testing or routine newborn screening for factor V Leiden mutation.
The ACMG does not recommend general screening for factor V Leiden mutation before administration of oral contraceptives. The ACMG recommends targeted testing prior to oral contraceptive use in women with a personal or family history of venous thrombosis.
Factor V Leiden screening of asymptomatic individuals with other recognized environmental risk factors, such as surgery, trauma, paralysis, and malignancy is not necessary or recommended by the ACMG, since all such individuals should receive appropriate medical prophylaxis for thrombosis regardless of carrier status. When Factor V Leiden testing is indicated, the ACMG recommends either direct DNA-based genotyping or factor V Leiden-specific functional assay (e.g., activated protein C (APC) resistance). Patients who test positive by a functional assay should then be further studied with the DNA test for confirmation and to distinguish heterozygotes from homozygotes. According to the ACMG, patients testing positive for factor V Leiden or APC resistance should be considered for molecular genetic testing for prothrombin 20210A, the most common thrombophilia with overlapping phenotype for which testing is easily and readily available. The prothrombin 20210A mutation is the second most common inherited clotting abnormality, occurring in 2 percent of the general population. It is only a mild risk factor for thrombosis, but may potentiate other risk factors (such as Factor V Leiden, oral contraceptives, surgery, trauma, etc.).
A factor V gene haplotype (HR2) defined by the R2 polymorphism (A4070G) may confer mild APC resistance and interact with the factor V Leiden mutation to produce a more severe APC resistance phenotype (Bernardi et al., 1997; de Visser et al., 2000; Mingozzi et al., 2003). In one study, co-inheritance of the HR2 haplotype increased the risk of venous thromboembolism associated with factor V Leiden by approximately threefold (Faioni et al., 1999). However, double heterozygosity for factor V Leiden and the R2 polymorphism was not associated with a significantly higher risk of early or late pregnancy loss than a heterozygous factor V Leiden mutation alone (Zammiti et al., 2006). Whether the HR2 haplotype alone is an independent thrombotic risk factor is still unclear. Several studies have suggested that the HR2 haplotype is associated with a two-fold increase in risk of venous thromboembolism (Alhenc-Gelas et al., 1999; Jadaon & Dashti 2005). In contrast, other studies (de Visser 2000; Luddington et al., 2000; Dindagur et al., 2006) found no significant increase in thrombotic risk (GeneTests, University of Washington, Seattle, 2007).
CADASIL
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a rare, genetically inherited, congenital vascular disease of the brain that causes strokes, subcortical dementia, migraine-like headaches, and psychiatric disturbances. CADASIL is very debilitating and symptoms usually surface around the age of 45. Although CADASIL can be treated with surgery to repair the defective blood vessels, patients often die by the age of 65. The exact incidence of CADASIL in the United States is unknown.
DNA testing for CADASIL is appropriate for symptomatic patients who have a family history consistent with an autosomal dominant pattern of inheritance of this condition. Clinical signs and symptoms of CADASIL include stroke, cognitive defects and/or dementia, migraine, and psychiatric disturbances. DNA testing is also indicated for presymptomatic patients where there is a family history consistent with an autosomal dominant pattern of inheritance and there is a known mutation in an affected member of the family. This policy is consistent with guidelines on CADASIL genetic testing from the European Federation of Neurological Societies.
Cystic Fibrosis
Cystic fibrosis is the most common potentially fatal autosomal recessive disease in the United States. It is characterized by chronic progressive disease of the respiratory system, malabsorption due to pancreatic insufficiency, increased loss of sodium and chloride in sweat, and male infertility as a consequence of atresia of the vas deferens. Pulmonary disease is the most common cause of mortality and morbidity in individuals with CF. The incidence of this disease ranges from 1:500 in Amish (Ohio) to 1:90,000 in Hawaiian Orientals, and is estimated to be 1:2,500 newborns of European ancestry. It occurs less frequently in people with other ethnic and racial backgrounds. About 1:25 persons of European ancestry is a carrier (or heterozygote), possessing one normal and one abnormal CF gene. Because of recent advances in clinical management of CF, babies born today are expected to live well into middle age.
Currently, the most frequently employed test for CF is the quantitative pilocarpine iontophoresis sweat test. Sweat chloride is more reliable than sweat sodium for diagnostic purposes with a sensitivity of 98% and a specificity of 83%. However, this test cannot detect CF carriers because the electrolyte content of sweat is normal in heterozygotes (Wallach, 1991). The gene for CF (cystic fibrosis trans-membrane conductance regulator, CFTR) was cloned, and the principal mutant gene in white people (DF508) was characterized in 1989. This mutation is due to a three-base-pair deletion that results in the loss of a phenylalanine at position 508 from the 1480-amino acid coding region (Riordan, et al., 1989). This mutation is found in approximately 70% of carriers of European ancestry, but the relative frequency varies from 30% in Ashkenazi Jews to 88% in Danes (Cutting, et al., 1992). Available evidence indicates that CFTR functions as a chloride channel, although it may also serve other functions. Since then, more than 200 CF mutations have been described. Five of the most common mutations (DF508, G542X, F551D, R553X, N1303K) constitute approximately 85 % of the alleles in the United States (Elias, et al., 1991). Thus, screening procedures that test for these 5 mutations will detect approximately 85% of CF carriers. The genetic screening test for CF is usually based on mouthwash samples collected by agitating sucrose or saline in the mouth. The DNA of these cells are amplified, digested, and subjected to separation techniques that identify 3 to 5 common mutations.
A National Institutes of Health consensus panel (1997) recommended that genetic testing for CF should be offered to adults with a positive family history of CF, to partners of people with the disease, to couples currently planning a pregnancy, and to couples seeking prenatal testing. However, the panel did not recommend genetic testing of CF to the general public or to newborn infants.
The American College of Obstetricians and Gynecologists (2001) has issued similar recommendations on genetic carrier testing for cystic fibrosis. ACOG recommends that obstetricians should offer CF screening to:
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Individuals with a family history of CF;
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Reproductive partners of people who have CF; and
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Couples in whom one or both members are white and who are planning a pregnancy or seeking prenatal care.
ACOG also recommends that screening should be made available to couples in other racial and ethnic groups. To date, over 900 mutations in the cystic fibrosis gene have been identified. As it is impractical to test for every known mutation, the American College of Medical Genetics Accreditation of Genetic Services Committee has compiled a standard screening panel of 25 cystic fibrosis mutations, which represents the standard panel that ACMG recommends for screening in the U.S. population (Grody, et al., 2001). This 25-mutation panel incorporates all CF-causing mutations with an allele frequency of greater than or equal to 0.1% in the general U.S. population, including mutation subsets shown to be sufficiently predominant in certain ethnic groups, such as Ashkenazi Jews and African Americans. This standard panel of mutations is intended to provide the greatest pan-ethnic detectability that can practically be performed.
Fragile X Syndrome
Fragile X syndrome is the most common cause of inherited mental retardation, seen in approximately one in 1,200 males and one in 2,500 females. Phenotypic abnormalities associated with Fragile X syndrome include mental retardation, autistic behaviors, characteristic narrow face with large jaw, and speech and language disorders. Fragile X syndrome was originally thought to be transmitted in an X-linked recessive manner; however, the inheritance pattern of fragile X syndrome has been shown to be much more complex.
Standard chromosomal analysis does not consistently demonstrate the cytogenetic abnormality in patients with fragile X syndrome, and molecular diagnostic techniques (DNA testing) have become the diagnostic procedure of choice for fragile X syndrome.
Aetna's policy on coverage of fragile X genetic testing is based on guidelines from the American College of Medical Genetics (1994) and the American College of Obstetricians and Gynecologists (1995).
Lactose Intolerance
Lactase-phlorizin hydrolase, which hydrolyzes lactose, the major carbohydrate in milk, plays a critical role in the nutrition of the mammalian neonate (Montgomery, et al., 1991). Lactose intolerance in adult humans is common, usually due to low levels of small intestinal lactase. Low lactase levels result from either intestinal injury or (in the majority of the world's adult population) alterations in the genetic expression of lactase. Although the mechanism of decreased lactase levels has been the subject of intensive investigation, no consensus has yet emerged.
The LactoTYPE Test (Prometheus Laboratories) is a blood test that is intended to identify patients with genetic-based lactose intolerance. According to the manufacturer, this test provides a more definitive diagnosis and scientific explanation for patients with persistent symptoms.
There is insufficient evidence that the assessment of the genetic etiology of lactose intolerance would affect the management of patients such that clinical outcomes are improved. Current guidelines on the management of lactose intolerance do not indicate that genetic testing is indicated (NHS, 2005; National Public Health Service for Wales, 2005).
Long QT Syndrome
Voltage-gated sodium channels are transmembrane proteins that produce the ionic current responsible for the rising phase of the cardiac action potential and play an important role in the initiation, propagation, and maintenance of normal cardiac rhythm. Inherited mutations in the sodium channel alpha-subunit gene (SCN5A), the gene encoding the pore-forming subunit of the cardiac sodium channel, have been associated with distinct cardiac rhythm syndromes such as the congenital long QT3 syndrome (LQT3), Brugada syndrome, isolated conduction disease, sudden unexpected nocturnal death syndrome (SUNDS), and sudden infant death syndrome (SIDS). Electrophysiological characterization of heterologously expressed mutant sodium channels have revealed gating defects that, in many cases, can explain the distinct phenotype associated with the rhythm disorder.
The long QT syndrome (LQTS) is a familial disease characterized by an abnormally prolonged QT interval and, usually, by stress-mediated life-threatening ventricular arrhythmias (Priori, et al., 2001). Characteristically, the first clinical manifestations of LQTS tend to appear during childhood or in teenagers. Two variants of LQTS have been described: a rare recessive form with congenital deafness (Jervell and Lange-Nielsen syndrome, J-LN), and a more frequent autosomal dominant form (Romano-Ward syndrome, RW). Five genes encoding subunits of cardiac ion channels have been associated to LQTS and genotype-phenotype correlation has been identified. Of the five genetic variants of LQTS currently identified, LQT1 and LQT2 subtypes involve two genes, KCNQ1 and HERG, which encode major potassium currents. LQT3 involves SCN5A, the gene encoding the cardiac sodium current. LQT5 and LQT6 are rare subtypes also involving the major potassium currents.
The principal diagnostic and phenotypic hallmark of LQTS is abnormal prolongation of ventricular repolarization, measured as lengthening of the QT interval on the 12-lead ECG (Maron, et al., 1998). This is usually most easily identified in lead II or V1, V3, or V5, but all 12 leads should be examined and the longest QT interval used; care should also be taken to exclude the U wave from the QT measurement.
LQT3 appears to be the most malignant variant and may be the one less effectively managed by beta blockers. LQT1 and LQT2 have a higher frequency of syncopal events but their lethality is lower and the protection afforded by beta-blockers, particularly in LQT1, is much higher. The Jervell and Lange-Nielsen recessive variant is associated with very early clinical manifestations and a poorer prognosis than the Romano-Ward autosomal dominant form. The presence of syndactyly seems to represent a different genetic variant of LQTS also associated with a poor prognosis.
Guidelines on sudden cardiac death from the European College of Cardiology (Priori, et al., 2001) state that identification of specific genetic variants of LQTS are useful in risk stratification. The clinical variants presenting association of the cardiac phenotype with syndactyly or with deafness (Jervell and Lange-Nielsen syndrome) have a more severe prognosis. Genetic defects on the cardiac sodium channel gene (SCN5A) are also associated with higher risk of sudden cardiac death. In addition, identification of specific genetic variants may help in suggesting behavioral changes likely to reduce risk. LQT1 patients are at very high risk during exercise, particularly swimming. LQT2 patients are quite sensitive to loud noises, especially when they are asleep or resting.
Genetic testing for LQTS may be indicated in persons with first-degree relatives that have a defined mutation. Genetic testing may also be indicated in individuals with a prolonged QT interval on resting electrocardiogram (a corrected QT interval (QTc) of 470 msec in males and 480 msec in females) without an identifiable external cause for QTc prolongation. Common external causes of QTc prolongation are listed in the table below.
| Table: Common External Causes of Prolongation of QTc Interval |
| Bradycardia |
| Heart disease (heart failure, ischemia) |
| Hypocalcemia |
| Hypomagnesemia |
| Hypokalemia |
| Hypothyroidism |
| Antiarrhythmic medications (quinidine, procainamide, amiodarone, sotalol, and dofetilide) |
| Tricyclic and tetracyclic antidepressants (e.g., amitryptyline) |
| Erythromycin |
| Cisapride |
| Pimozide |
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Thioridazine
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Hereditary Hemochromatosis
Hemochromatosis, a condition involving excess accumulation of iron, can lead to iron overload, which in turn can result in complications such as cirrhosis, diabetes, cardiomyopathy, and arthritis (Burke, 1992; Hanson, et al., 2001).
Hereditary hemochromatosis (HHC) is characterized by inappropriately increased iron absorption from the duodenum and upper intestine, with consequent deposition in various parenchymal organs, notably the liver, pancreas, joints, heart, pituitary gland and skin, with resultant end-organ damage (Limdi & Crampton, 2004). Clinical features may be non-specific and include lethargy and malaise, or reflect target organ damage and present with abnormal liver tests, cirrhosis, diabetes mellitus, arthropathy, cardiomyopathy, skin pigmentation and gonadal failure. Early recognition and treatment (phlebotomy) is essential to prevent irreversible complications such as cirrhosis and hepatocellular carcinoma.
HHC is an autosomal recessive condition associated with mutations of the HFE gene. Two of the 37 allelic variants of the HFE gene, C282Y and H63D, are significantly correlated with HHC. C282Y is the more severe mutation, and homozygosity for the C282Y genotype accounts for the majority of clinically penetrant cases. Hanson, et al. (2001) reported that homozygosity for the C282Y mutation has been found in 52-100 percent of previous studies on clinically diagnosed index cases. Five percent of HHC probands were found by Hanson, et al. to be compound heterozygotes (C282Y/H63D), and 1.5% were homozygous for the H63D mutation; 3.6% were C282Y heterozygotes, and 5.2% were H63D heterozygotes. In 7% of cases, C282Y and H63D mutations were not present. In the general population, the frequency of the C282Y/C282Y genotype is 0.4%.
HHC is a very common genetic defect in the Caucasian population. C282Y heterozygosity ranges from 9.2% in Europeans to nil in Asian, Indian subcontinent, African, Middle Eastern, Australian and Asian populations (Hanson, et al., 2001). The H63D carrier frequency is 22% in European populations.
Accurate data on the penetrance of the different HFE genotypes are not available. But current data suggest that clinical disease does not develop in a substantial proportion of people with this genotype. Available data suggest that up to 38% to 50% of C282Y homozygotes may develop iron overload, with up to 10% to 33% eventually developing hemochromatosis-associated morbidity (Whitlock, et al. 2006). A pooled analysis found that patients with the HFE genotypes C282Y/H63D and H63D/H63D are also at increased risk for iron overload, yet overall, disease is likely to develop in fewer than 1 percent of people with these genotypes (Burke, 1992). Thus, DNA-based tests for hemochromatosis identify a genetic risk rather than the disease itself.
Environmental factors such as diet and exposure to alcohol or other hepatotoxins may modify the clinical outcome in patients with hemochromatosis, and variations in other genes affecting iron metabolism may also be a factor. As a result, the clinical condition of iron overload is most reliably diagnosed on the basis of biochemical evidence of excess body iron (Burke, 1992).
Whether it is beneficial to screen asymptomatic people for a genetic risk of iron overload is a matter of debate. To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible persons, laboratory standardization, and the potential for stigmatization or discrimination (Hanson, et al., 2001; Whitlock, et al., 2006). A systematic evidence review prepared for the U.S. Preventive Services Task Force concluded: "Research addressing genetic screening for hereditary hemochromatosis remains insufficient to confidently project the impact of, or estimate the benefit from, widespread or high-risk genetic screening for hereditary hemochromatosis" (Whitlock, et al., 2006).
Familial Nephrotic Syndrome (NPHS1, NPHS2)
Nephrotic syndrome comes in two variants -- those sensitive to treatment with immunosuppressants (steroid-sensitive), and those resistant to immunosuppressants (steroid-resistant). Familial forms of nephrotic syndrome are steroid resistant (Niaudet, 2007).Mutations in two genes, NPHS1 and NPHS2, have been associated with a familial nephrotic syndrome. Mutations in the gene for podocin, called NPHS2, also known as familial focal glomerulosclerosis, are observed in patients with both familial and sporadic steroid-resistant nephrotic syndrome (SRNS).
Identifying children with nephrotic syndrome due to NPHS2 mutations can avoid unnecessary exposure to immunosuppressive therapy, because immunosuppressive therapy has not been shown to be effective in treating these children (Niaudet, 2007). Thus, authorities have recommended testing for such mutations in those with a familial history of steroid resistant nephrotic syndrome and children with steroid-resistant disease .
Some have suggested that, to avoid unnecessary exposure to steroid therapy, all children with a first episode of the nephrotic syndrome should be screened for NPHS2 mutations (Niaudet, 2007). However, given that over 85 percent of children with idiopathic nephrotic syndrome are steroid-sensitive and only approximately 20 percent of steroid-resistant patients have NPHS2 mutations, screening for abnormalities at this genetic locus would identify less than 5 percent of all cases. However, screening a child with a first episode of the nephrotic syndrome with a familial history of steroid-resistant nephrotic syndrome has been recommended because they are at increased risk for having a NPHS2 gene mutation.
Mutations in the gene for nephrin, called NPHS1, cause the congenital nephrotic syndrome of Finnish type (CNF) (Niaudet, 2007). CNF is inherited as an autosomal recessive trait, with both sexes being involved equally. There are no manifestations of the disease in heterozygous individuals.Most infants with the CNF are born prematurely (35 to 38 weeks), with a low birth weight for gestational age. Edema is present at birth or appears during the first week of life in one-half of cases. Severe nephrotic syndrome with marked ascites is always present by three months. End-stage renal failure usually occurs between three and eight years of age. Prolonged survival is possible with aggressive supportive treatment, including dialysis and renal transplantation.
The nephrotic syndrome in CNF is always resistant to corticosteroids and immunosuppressive drugs, since this is not an immunologic disease (Niaudet, 2007). Furthermore these drugs may be harmful due to affected individuals' already high susceptibility to infection.
The CNF becomes manifest during early fetal life, beginning at the gestation age of 15 to 16 weeks. The initial symptom is fetal proteinuria, which leads to a more than 10-fold increase in the amniotic fluid alpha-fetoprotein (AFP) concentration (Niaudet, 2007). A parallel, but less important increase in the maternal plasma AFP level is observed. These changes are not specific, but they may permit the antenatal diagnosis of CNF in high risk families in which termination of the pregnancy might be considered. However, false positive results do occur, often leading to abortion of healthy fetuses.
Genetic linkage and haplotype analyses may diminish the risk of false positive results in informative families (Niaudet, 2007). The four major haplotypes, which cover 90 percent of the CNF alleles in Finland, have been identified, resulting in a test with up to 95 percent accuracy.
Authorities do not recommend screening for NPHS1 mutations for all children with the first episode of nephrotic syndrome, for the reasons noted above regarding NPHS2 mutation screening. However, genetic testing may be indicated for infants with congenital nephrotic syndrome (i.e., appearing within the first months of life) who are of Finnish descent and/or who have a family history that suggests a familial cause of congenital nephrotic syndrome. The primary purpose of this testing is for pregnancy planning. Detection of an NPHS1 mutation also has therapeutic implications, as such nephrotic syndrome is steroid resistant.
Primary Dystonia (DYT-1)
Dystonia consists of repetitive, patterned, twisting, and sustained movements that may be either slow or rapid. Dystonic states are classified as primary, secondary, or psychogenic depending upon the cause (Jankovic, 2007). By definition, primary dystonia is associated with no other neurologic impairment, such as intellectual, pyramidal, cerebellar, or sensory deficits. Cerebral palsy is the most common cause of secondary dystonia.
Primary dystonia may be sporadic or inherited (Jankovic, 2007). Cases with onset in childhood usually are inherited in an autosomal dominant pattern. Many patients with hereditary dystonia have a mutation in the TOR1A (DYT1) gene that encodes the protein torsinA, an ATP-binding protein in the 9q34 locus. The role of torsinA in the pathogenesis of primary dystonia is unknown. DNA testing for the abnormal TOR1A gene can be performed on individuals with dystonia. The purpose of such testing is to help rule out secondary or psychogenic causes of dystonia, and for family planning purposes.
Malignant Melanoma
An estimated 8 to 12 percent of persons with melanoma have a family history of the disease, but not all of these individuals have hereditary melanoma (Tsao & Haluska, 2007). In some cases, the apparent familial inheritance pattern may be due to clustering of sporadic cases in families with common heavy sun exposure and susceptible skin type.
A melanoma susceptibility locus has been identified on chromosome 9p21; this has been designated CDKN2A (also known as MTS1 (multiple tumor suppressor 1)) (Tsao & Haluska, 2007), There is a variable rate of CDKN2A mutations in patients with hereditary melanoma. The risk of CDKN2A mutation varies from approximately 10 percent for families with at least two relatives having melanoma, to more than 40 percent for families having multiple affected first degree relatives spanning several generations.
Persons at increased risk of melanoma are managed with close clinical surveillance and education in risk-reduction behavior (eg, sun avoidance, sunscreen use). It is unclear how CDKN2A genetic test information would alter clinical recommendations (Tsao & Haluska, 2007). The negative predictive value of a negative test for a CDKN2A mutation is also not established since many familial cases occur in the absence of CDKN2A mutations. It is estimated that the prevalence of CDKN2A mutation carriers is less than 1 percent in high incidence populations. Thus, no mutations will be identifiable in the majority of families presenting to clinical geneticists.
The American Society of Clinical Oncology (ASCO) has issued a consensus report on the utility of genetic testing for cancer susceptibility (ASCO, 1996), and recommendations for the process of genetic testing were updated in 2003 (ASCO, 2003). The report notes that the sensitivity and specificity of the commercially available test for CDKN2A mutations are not fully known. Because of the difficulties with interpretation of the genetic tests, and because test results do not alter patient or family member management, ASCO recommends that CDKN2A testing be performed only in the context of a clinical trial.
The Scottish Intercollegiate Guidelines Network (SIGN, 2003) protocols on management of cutaneous melanoma reached similar conclusions, stating that "[g]enetic testing in familial or sporadic melanoma is not appropriate in a routine clinical setting and should only be undertaken in the context of appropriate research studies."
The Melanoma Genetics Consortium recommends that genetic testing for melanoma susceptibility should not be offered outside of a research setting (Kefford, et al., 2002). They state that “[u]ntil further data become available, however, clinical evaluation of risk remains the gold standard for preventing melanoma. First-degree relatives of individuals at high risk should be engaged in the same programmes of melanoma prevention and surveillance irrespective of the results of any genetic testing.”
Charcot-Marie Tooth Disease Type 1A (PMP-22)
Charcot Marie Tooth disease, also known as peroneal muscular atrophy, progressive neural muscular atrophy, as well as hereditary motor and sensory neuropathy, is one of the three major types of hereditary neuropathy. With an estimated prevalence of at least 1:2,500 (autosomal dominance), CMT is one of the most common genetic neuromuscular disorders affecting approximately 125,000 persons in the United States. This hereditary peripheral neuropathy is genetically and clinically heterogeneous. It is usually inherited in an autosomal dominant manner, and occasionally in an autosomal recessive manner. Sporadic as well as X-linked cases have also been reported. In the X-linked recessive patterns, only males develop the disease, although females who inherit the defective gene can pass the disease onto their sons. In the X-linked dominant pattern, an affected mother can pass on the disorder to both sons and daughters, while an affected father can only pass it onto his daughters. The clinical manifestations can vary greatly in severity and age of onset. The clinical features may be so mild that they may be undetectable by patients, their families and physicians.
Charcot-Marie-Tooth disease is usually diagnosed by an extensive physical examination, assessing characteristic weakness in the foot, leg, and hand, as well as deformities and impaired function in walking and manual manipulation. The clinical diagnosis is then confirmed by electromyogramand nerve conduction velocity tests, and sometimes by biopsy of muscle and of sural cutaneous nerve. Since CMT is a hereditary disease, family history can also help to confirm the diagnosis. Based on studies of motor nerve conduction velocity, CMT can be further classified into two types: (i) CMT Type I -- slow conduction velocity (less than 40 meters per second for the median nerve or less than 15 meters per second for the peroneal nerve) which accounts for 70% of all CMT cases, and (ii) CMT Type II -- normal or near normal nerve conduction velocity with decreased amplitude which accounts for the remaining 30% of CMT cases. Charcot Marie Tooth Type I disease is a demyelinating neuropathy with hypertrophic changes in peripheral nerves, and has its onset usually during late childhood. On the other hand, CMT Type II is a non-demyelinating neuronal disorder without hypertrophic changes, and has its onset generally during adolescence.
Both CMT Types I and II are characterized by a slow degeneration of peripheral nerves and roots, resulting in distal muscle atrophy commencing in the lower extremities, and affecting the upper extremities several years later. Symptoms include foot drop or clubfoot, paresthesia in legs, sloping gait, later weakness and atrophy of hands, then arms, absence or reduction of deep tendon reflexes, and occasionally mild sensory loss. Charcot Marie Tooth disease is not a fatal disorder. It does not shorten the normal life expectancy of patients, and it does not affect them mentally. As stated earlier, there is a wide range of variation in the clinical manifestations of CMT -- the degree of severity can vary considerably from patient to patient, even among affected family members within the same generation. The condition can range from having no problems to having major difficulties in ambulation in early adult life, however, the latter is unusual. Most patients are able to ambulate and have gainful employment until old age. Currently, there is no specific treatment for this disease. Management of the majority of patients with CMT disease consists of supportive care with emphasis on proper bracing, foot care, physical therapy and occupational counseling. For example, the legs and shoes can be fitted with light braces and springs, respectively, to overcome foot drop. If foot drop is severe and the disease has become stationary, the ankle can be stabilized by arthrodeses.
The underlying genetic basis for CMT Type I has been characterized. A point mutation in the PMP22 gene which encodes a peripheral myelin protein with an apparent molecular weight of 22,000 or a DNA duplication of a specific region.5 megabases) including the PMP22 gene in the proximal short arm of chromosome 17 (band 17p11.2-p12) has been identified in 70% of clinically diagnosed patients --- CMT Type IA. Thus, patients with CMT Type IA represent approximately 50% of all CMT cases. Other CMT Type I patients (CMT Type IB) exhibit an abnormality (Duffy locus) in the proximal long arm of chromosome number 1 (band 1q21-22). Presently, no test is available for the dominant CMTIB gene on chromosome 1. On the other hand, a CMT Type IA DNA test is available commercially. The test is accomplished through a blood sample analysis -- DNAs are extracted from leukocytes of patients and pulsed-field gel electrophoresis is employed to isolate large segments of DNA encompassing CMTIA duplication-specific junction fragments which are then detected by hybridization with aCMTIA duplication-specific probe (CMTIA-REP). This probe identifies the homologous regions that flank the CMTIA duplication monomer unit.
A positive CMTIA DNA test means the presence of a 500 kilobases CMTIA duplication specific junction fragment, and is diagnostic for CMT Type IA. A negative CMT Type IA means the absence of the CMTIA duplication specific junction fragment, and does not rule out a diagnosis of CMT disease. This is because patients with CMT Type IA represent approximately 50% of all CMT cases. The value of this molecular test in family planning is questionable because of its relatively low detection rate and its inability to predict the severity of the disease. Moreover, it is likely that there are undiscovered CMTI genes since there are dominant CMTI pedigrees who do not have abnormalities at the known chromosome 1 and 17 locations (CMT Type IC). In addition, other investigators have reported X-linked forms of CMTI at the region of Xq13-21, and Xq26.
Since CMT is not life-threatening, rarely severely disabling, and has no specific treatment, it is unclear how the results of this CMT Type I DNA test, which can not predict the severity of the disease, would affect family planning. Moreover, because of its low detection rate, the CMT Type I DNA test appears to be inferior to the conventional means of diagnosis through physical examination, family history, electromyography and nerve conduction velocity studies. Thus, the sole value of genetic testing for CMTIA is to establish the diagnosis and to distinguish this from other causes of neuropathy.
Familial Amyotrophic Lateral Sclerosis (SOD1 Mutation)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both the upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographical representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. In the early stage of the disease, the clinical aspects of ALS can vary. Affected individuals typically present with asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings include muscle fasciculations, muscle cramps, and lability of affect but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. Approximately 5,000 people in the U.S. are diagnosed with amyotrophic lateral sclerosis each year.
Most people with ALS have a form of the condition that is described as sporadic or noninherited. The cause of sporadic ALS is largely unknown but probably involves a combination of genetic and environmental factors. About 10 % of people with ALS have a familial form of the condition, which is caused by an inherited genetic mutation, usually as an autosomal dominant trait. The mean age of onset of ALS in individuals with no known family history is 56 years and in familial ALS it is 46 years.
The diagnosis of ALS is based on clinical features, electrodiagnostic testing (EMG), and exclusion of other health conditions with related symptoms. At present, genetic testing in ALS has no value in making the diagnosis. The only genetic test currently available detects the SOD1 mutation. Since only 20 % of familial ALS patients will test positively for an SOD1 mutation, this test has limited value in genetic counseling.
Migrainous Vertigo
Migrainous vertigo is a term used to describe episodic vertigo in patients with a history of migraines or with other clinical features of migraine. Approximately 20 - 33 % of migraine patients experience episodic vertigo. The underlying cause of migrainous vertigo is not very well understood. There are no confirmatory diagnostic tests or susceptible genes associated with migrainous vertigo. Other conditions, specifically Meniere's disease and structural and vascular brainstem disease, must be excluded (Black, 2006).
Prostate Cancer
At this time, there are no susceptibility genes that have been unequivocally associated with prostate cancer predisposition. Genetic testing for prostate cancer is currently available only within the context of a research study.
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