Familial Hypercholesterolemia (FH)

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1 Familial Hypercholesterolemia (FH) Genetic Testing patient guide

2 What is Familial Hypercholesterolemia? Familial hypercholesterolemia or high cholesterol (FH) is a genetic condition that causes lifelong levels of extremely high cholesterol, which can lead to early coronary artery disease (CAD). CAD happens when the major blood vessels that supply your heart with blood and oxygen (called the coronary arteries) become damaged or diseased. Cholesterolcontaining deposits called plaque in your arteries lead to CAD. CAD can include angina (also known as chest pain) and myocardial infarction (also known as a heart attack). If you or someone in your family has FH, you are not alone. About 1 in 250 people has the condition, but about 90% of them do not know they have it. There are two forms of FH: heterozygous FH (HeFH) and homozygous FH (HoFH). People with HeFH have one gene mutation that causes them to develop FH. They have a 20-times increased risk for early CAD, if they do not get treatment for it. Many people with HeFH already have chest pain or have had a heart attack before they are diagnosed with FH. People with HoFH have two gene mutations that cause them to develop FH. They have extremely high cholesterol levels, and usually develop much earlier CAD, if not treated properly. Other Symptoms of FH: Collections of cholesterol (deposits) can cause physical signs of FH on the body. One place these can occur is on tendons. These may first look like thickening of a tendon, and then later as a yellowish deposit on a tendon or tendons. These may occur on the Achilles tendon and also on the hands, feet, elbows and knees. Cholesterol deposits can also occur in the eye. Corneal arcus results from cholesterol collecting around the rim of the cornea. Corneal arcus only points to FH if it is seen in people under age 45. Having physical signs of FH on your body increases the chances that you have FH. However, having none of them does not mean you don t have it many people with FH have no physical signs at all. As well, sometimes there are no symptoms or physical signs of FH until the disease has progressed and gotten quite severe in someone. This may lead to a sudden heart attack or sudden cardiac arrest due to underlying heart disease.

3 Medical guidelines suggest that anyone with a cholesterol level falling within the ranges shown in the table below (when not receiving treatment) be evaluated for possible FH. When a doctor orders a cholesterol test, your total cholesterol, LDL cholesterol (the bad cholesterol), HDL cholesterol (the good cholesterol), and triglycerides are measured. If you have very high cholesterol, you should tell your doctor about any family history of high cholesterol or heart disease to learn more about FH. if you have a cholesterol level in these ranges, talk to your doctor People 20 years of age or older People under 20 years of age ldl cholesterol total cholesterol 190 mg/dl 220 mg/dl 160 mg/dl 190 mg/dl What Causes FH? Genes are instructions for how our bodies work and develop. Everyone has two copies of each gene. We get one copy of each gene from each of our parents. Most people with FH have a mutation (change in the gene, like a spelling mistake in one of three genes: LDLR, APOB, and PCSK9. These genes are important for making proteins that help take cholesterol out of our blood. Mutations in these genes make them not work properly. How Likely is it that Genetic Testing Will Find a Mutation? If you have FH, there is up to an 70% chance that genetic testing will find the gene mutation causing it. When a diagnosis of FH is unclear, the chance that a genetic test will identify the cause is between 35-60%. genes implicated in familial hypercholesterolemia PCSK9 APOB Unknown LDLR Mutations in 3 genes have been identified in most cases of FH. LDLR accounts for over 85% of known genetic causes.

4 How Does FH Run in Families? FH is inherited, and runs in families in an autosomal dominant inheritance pattern. This means it affects both men and women equally, and it takes just one gene mutation for a person to develop FH. People with one mutation have heterozygous FH (HeFH). People with two mutations have homozygous FH (HoFH). For people with HeFH, each of their close relatives (mother, father, brothers, sisters, and children) has a 50/50 chance to also have the same FH gene mutation (pictured below). For people with two FH gene mutations, they likely inherited a mutation from both their mother and father. Has gene mutation Does not have gene mutation notes

5 Is FH Genetic Testing Right for Me? Here are some ways that genetic testing for FH may help you or your family: Genetic testing may confirm your diagnosis of FH and allow your doctor to rule out other possible medical conditions Genetic testing may help your doctor begin the right treatment immediately to help lower your cholesterol Certain FH gene mutations may be more severe than others. Genetic testing may provide information about how your symptoms of FH will be over time. If genetic testing finds a gene mutation in you, this test result could allow your family (including children) to be tested for the same mutation, if they wish. Finding family members that are at risk for FH before they have symptoms could make it easier to manage and help them get immediate treatment. Cholesterol testing should be considered in at-risk family members as young as 2 years of age. However, learning information from genetic testing can cause worry and anxiety for some. Please talk to your doctor or genetic counselor about any questions or concerns you have before you have testing, and during the process. While many issues are reviewed in this booklet, this information is meant to add to a talk you have with your doctor or genetic counselor. notes

6 What Do My Results Mean? If you have genetic testing, you will receive one of three possible results in your test report. Below are explanations of these results, which you should discuss with your doctor or genetic counselor. results Positive Negative Variant of Unknown Significance (VUS) explanation A mutation(s) was found in a gene that causes FH This confirms your diagnosis of FH Your family members can now be tested for this same mutation, if they would like Your testing did not find any gene mutations that cause FH. This does not change your diagnosis. If you have been diagnosed with FH, that remains the same Your medical treatment and screening should be based on your personal and family history You may still have a mutation in a gene not included in this test. Talk with your doctor or genetic counselor about whether more genetic testing is right for you A genetic change was found, but we do not know if it causes FH or not. This does not change your diagnosis. If you have been diagnosed with FH that remains the same Talk with your doctor or genetic counselor about whether more genetic testing is right for you or your family. Testing for your family members with similar health problems may help explain this VUS Your medical treatment and screening should be based on your personal and family history notes

7 What Should I Tell My Family Members About FH? If you have FH, you should tell all your close family members (such as your brothers, sisters, parents, children) to ask their doctor to check their cholesterol levels. If you have genetic testing showing you have a gene mutation that causes FH, you should tell your family members so they can consider having genetic testing themselves. For children with a family history of very high cholesterol or early-onset heart disease (before age 55 for men or before age 65 for women) cholesterol testing should be considered as young as 2 years of age. Early treatment can make a difference to keep you and your family members healthy. Has FH Should talk to doctor about cholesterol screening notes

8 FAQs About Genetic Testing q1. how does genetic testing work? Genetic testing is done using a blood or saliva sample (other sample types may also be used please see ambrygen.com for details). Your sample is sent overnight in a special kit to Ambry (all organized by your doctor or genetic counselor). Once your sample and paperwork arrive at Ambry, your testing begins. Results usually take 3-8 weeks and will be sent to your doctor or genetic counselor, who will talk with you about them. q2. can genetic testing results be used against me? In the U.S., the Genetic Information Nondiscrimination Act (2008) prohibits discrimination by health insurance companies and employers based on genetic information. Depending on where you live in the world, you may have different (or fewer) laws in this area. q3. how should i tell my relatives about my genetic test results? There are many ways to share genetic test results. You and your family may choose to share them by phone call, visiting in person, letter, or . It can sometimes be tricky because genetic testing is a very personal process, and everyone reacts to this type of news differently. Your doctor or genetic counselor can help you come up with a plan to tell your family members, in a way that works best for all of you. notes

9 Test Result and Recommendations To be completed by you and your doctor or genetic counselor, when you receive your genetic test results and medical management recommendations test result Negative: No mutation found Positive: Mutation(s) found in gene Variant of unknown significance found in gene recommendations for you recommendations for family members Genetic testing is recommended for family members to consider Genetic testing is not available or recommended for family members

10 FAQs about Billing and Insurance q1. what is ambry s billing policy? Ambry offers a variety of payment options. Many insurance plans cover genetic testing and Ambry is contracted with the majority of U.S. health plans. Your out-of-pocket cost may vary based on your individual plan. We offer personalized verification of insurance coverage and financial options for your genetic testing. A team of dedicated specialists is available to help you get access to the genetic testing you need and answer any questions you have about our payment options. Call or our Billing department at or billing@ambrygen.com with any questions. q2. what is an explanation of benefits (eob)? It is not a bill and does not require payment. Your insurance company sends you an EOB to explain any services paid on your behalf. You can contact us directly to speak with a Billing specialist with any questions/ concerns about your EOB. Some genetic tests take weeks to process to receive the best results. In addition, insurance companies can take over two months to process claims, and longer if we need to send information again, and this could delay your bill. q3. how much do ambry s tests cost? We are committed to making the genetic testing process as simple and cost-effective as possible. Prices depend on if your insurance plan is contracted with Ambry, and if they are a private or public plan. We also offer prices when someone pays by cash, or when an institution pays. This not necessarily what is reflected on an EOB, so please contact us directly to speak with a Billing specialist with any questions/concerns. q4. why did i receive a bill more than a month after my test? Some genetic tests take weeks to process to receive the best results. In addition, insurance companies can take over two months to process claims, and longer if we need to send information again. All of this could delay your bill, but we try our best to prevent this from happening.

11 Resources for Patients These and other resources can help build a sense of community and help answer some common questions. ambry s cardiology site for families patients.ambrygen.com/cardiology the fh foundation thefhfoundation.org genetic information nondiscrimination act (gina) ginahelp.org the national lipid association Find a Genetic Counselor national society of genetic counselors nsgc.org canadian association of genetic counsellors cagc-accg.ca About Ambry Ambry is a genetics-based healthcare company that is dedicated to open scientific exchange so we can work together to understand and treat all human disease faster. ambry genetics 15 Argonaut Aliso Viejo, CA USA +1 (866) info@ambrygen.com For more details about these tests, visit ambrygen.com

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