to Elder Law and Special Needs Planning Attorneys
By Kelli Swan, MS, and Jaellah S. Thalberg, MSI. Introduction ... 104
II. Newborn Screening ... 104
A. Case: Steve and Molly ... 105
1. Genetics of PKU ... 105
2. Newborn Screening for PKU ... 106
3. Reproductive Decisions ... 106
B. Case: Mike and Tanya ... 107
1. Genetics of Hearing Loss ... 107
2. Newborn Screening for Hearing Loss ... 107
3. Is Deafness a Disability? ... 108
III. Noninvasive Prenatal Screening... 109
A. Case: Altan ... 109
1. The Technology of Noninvasive Prenatal Screening ... 109
2. Prenatal Testing for Down Syndrome ... 110
3. Standardization of Testing for Down Syndrome During Pregnancy... 111
4. Noninvasive Prenatal Screening and Down Syndrome ... 111
IV. Hereditary Cancers ... 112
A. Case: Susan ... 112
1. Genetics of Hereditary Breast and Ovarian Cancer Syndrome ... 112
2. “Previvor” Concept ... 113
3. Affordable Care Act and BRCA Testing ... 114
V. Alzheimer’s Disease ... 114
A. Case: Shira ... 114
1. Brief Genetic Background of Alzheimer’s Disease ... 114
2. The Right Test for the Right History ... 115
3. Informed Consent ... 116
4. Genetic Information Nondiscrimination Act and Insurance ... 117
VI. Conclusion ... 117
Endnotes ... 118
Kelli Swan, MS, is a diplomat of the American Board of Genetic Counseling and a board certified genetic coun-selor. She received an M.S. in Genetic Counseling from Northwestern University in 2009 and an M.A. in Medical Humanities and Bioethics from Northwestern University in 2011. She specializes in cancer genetics and works for Myriad Genetics, Inc., in Salt Lake City, as a Regional Medical Specialist. She is also a member of the National Society of Genetic Counselors’ Ethics Advisory Group.
Jaellah S. Thalberg, MS, is a diplomat of the American Board of Genetic Counseling and a board certified ge-netic counselor. She received an M.S. in Gege-netic Counseling from Northwestern University in 2012 and an M.A. in Medical Humanities and Bioethics from Northwestern University in 2014. She specializes in prenatal genetics and works for the Legacy Health system in Portland, Oregon.
I. Introduction
Gregory Wilcox and Rachel Koff aptly note in their article in this issue of NAELA Journal, “Genetics is no longer only a topic for biology courses and science magazines; it can be used to great effect in individuals.” Genetic testing has evolved from being the subject of science fiction novels into a standard of care in American health care. Routine genetic test-ing begins at birth, when nearly all babies are screened for a variety of genetic conditions. Continuing throughout adulthood, an increasing number of individuals are being exposed to genetics and genetic testing. One’s genetic information can help direct his or her medical care and management throughout all stages of life.
Evidence that genetic testing is becoming a standard of care is illustrated by many professional society guidelines. The American College of Medical Genetics and Genomics (ACMG) advocates that individuals with a cognitive impairment or individuals diagnosed on the autism spectrum undergo a genetic evaluation [1-3].* The American College of Obstetri-cians and Gynecologists (ACOG) recommends that all pregnant women be offered genetic testing for conditions such as Down syndrome or cystic fibrosis [4, 5]. The National Com-prehensive Cancer Network (NCCN) recommends that women diagnosed with breast cancer at or under the age of 45 and women diagnosed with ovarian cancer be offered testing for the “breast cancer genes,” BRCA1 and BRCA2, which can help guide surgery and treatment options [6].
While professional societies’ guidelines have cemented genetic testing’s role in the medical community, mainstream media coverage of genetic conditions has increased genetic testing awareness in the general public. Growing awareness of and technological advances in genetic testing make it very likely that Elder Law attorneys will work with clients who have experienced genetic testing and/or genetic conditions in some way. The authors hope that this article will help Elder Law attorneys better understand the uses, benefits, and limitations of genetic testing to help them support such clients. Developing this understanding will become even more important as genetic technologies evolve.
In this article, which is intended to supplement the article in this issue written by Wil-cox and Koff, five fictional case examples illustrate the value of genetic information in our lives and highlight certain issues that may be of interest to Elder Law attorneys.
Our dive into genetic testing begins with an explanation of newborn screening, which is designed to identify newborns with specific diseases or disabilities and thus enable prompt treatment. Next, we consider how newborn screening has expanded to include conditions such as hearing loss and deafness, which raises the question of how one defines disability. We then explore cultural views on disability by considering prenatal genetic testing recommenda-tions for Down syndrome using the newly available noninvasive prenatal screening (NIPS) and how this technology might impact Down syndrome in the future. Finally, we consider the utility of genetic testing for adult-onset conditions, such as breast and ovarian cancer and Alzheimer’s disease.
II. Newborn Screening
More than 50 years ago, screening of newborn babies for select medical conditions * Note about the citations in this article: The authors use end notes consistent with the Annotated EndNote X7
began to make its way into routine medical care. Beginning with just one disorder, phenyl-ketonuria (PKU), newborn screening has expanded to include more than 50 conditions, with the specific panel of newborn disorders screened for varying from state to state [7]. This routine testing involves analyzing the newborn’s blood, which is collected from a heel stick shortly after birth (typically around 24 hours of age).
Newborn screening is not used for diagnosing these genetic conditions. When a new-born receives a positive screen, the family is contacted to coordinate follow-up testing to confirm or rule out the disorder. If a diagnosis is confirmed, prompt treatment is started.
Newborn screening strives to achieve the fundamental goal of reduced mortality, mor-bidity, and disability in the screened infant by fostering early detection, diagnosis, and treat-ment of certain disorders [7, 8]. Newborn screening has been praised as being a victory of medicine. As we attempt to show the value of newborn screening, we also hope to illustrate some of the more complex issues of newborn screening that challenge the perception of what constitutes a disability and what disorders require prompt treatment.
A. Case: Steve and Molly
Steve and Molly are proud new parents of their first child, Emma. When Emma is 8 days old, they receive a phone call from the local hospital informing them that Emma’s new-born screen came back positive for the genetic condition PKU. They are referred to a local genetics clinic, and additional testing confirms that Emma has PKU. Emma is started on a special formula and diet that will prevent her from developing mental retardation, which can result from PKU.
1. Genetics of PKU
PKU is a rare inherited disorder affecting approximately 1 in 15,000 people. In the United States, approximately 275 infants will be born with the disease per year [9]. In the hu-man body, proteins perform most of the work in our cells and are required for the structure, function, and regulation of the body’s tissues and organs. Amino acids, usually obtained from the food we eat, are the building blocks of protein. PKU is a metabolic disorder that results in the inability of the body to use the amino acid phenylalanine (Phe). Normally, the body uses an enzyme called phenylalanine hydroxylase (PAH) to convert Phe to another amino acid, tyrosine. Someone with PKU lacks the PAH enzyme, which results in Phe accumulating in the blood and tissues because it cannot be converted tyrosine. High Phe levels are toxic to the central nervous system and can cause severe complications. If left untreated, PKU can cause irreversible mental retardation, hyperactivity, autistic-like features, and seizures [10, 11].
Newborns such as Emma who are diagnosed with PKU are immediately started on a specific lifelong diet. Although some Phe is needed for normal growth, the diet consists of foods low in Phe, and Phe levels are measured periodically. High-protein foods are avoided, and special Phe-free formulas are available for all age groups [11]. The goal of this diet is to maintain normal Phe levels in the body. Until 2007, a low-Phe diet was the only treatment for PKU. In 2007, the U.S. Food and Drug Administration (FDA) approved Kuvan, a pre-scription medication that works to stimulate PAH enzyme activity and thus lowers Phe levels in the body. This medication may not be effective in all patients with PKU, but it provides another option for maintaining normal Phe levels in conjunction with the low-Phe diet [12].
When treatment is started early and strictly maintained, children with PKU can be expected to achieve normal development and live a normal lifespan.
Mutations in the PAH gene cause PKU, an autosomal recessive condition. Individuals who have PKU have two PAH mutations, one inherited from the mother and one inherited from the father. Thus, when a baby such as Emma is diagnosed with PKU, we also learn that both parents are carriers of PKU. This means that each parent has one PAH mutation. Car-riers such as Steve and Molly do not have PKU but are at risk for having children with this condition. It is estimated that approximately 1 in 50 people are carriers of PKU. Because Steve and Molly are PKU carriers, they have a 25 percent chance of having another child with PKU with each future pregnancy.
2. Newborn Screening for PKU
Newborn screening for PKU is performed by determining the Phe levels in the newborn’s blood, which is obtained during a heel stick. Virtually 100 percent of PKU cases can be de-tected by newborn screening [13]. Newborn screening for PKU is widely viewed as a “victory for scientific medicine” [9]. If PKU is detected in the newborn, treatment with a low-Phe diet successfully averts the complications and cognitive impairment caused by PKU. All 50 states currently require newborn screening for PKU. Outside the United States, newborn screening for PKU has become routine in nearly every industrialized nation and has extended into many poorer countries [7, 9]. Because newborns with PKU appear normal, routine screening of all newborns enables early identification of the disorder and prevention of disability. Children such as Emma can now experience normal development and become productive adults[14]. 3. Reproductive Decisions
Steve and Molly learned that they are PKU carriers when Emma was diagnosed and have a 25 percent chance of having another child with PKU with each pregnancy. Because they want more children, Steve and Molly decided to pursue testing of the PAH gene, which enables the identification of the specific mutations in the gene they carry. Being able to identify these specific mutations gives Steve and Molly the information they need to make informed reproductive decisions. Stuart Lavery, at IVF Hammersmith Hospital in London, and colleagues describe the decisions such families face when considering starting or enlarg-ing their families [15].
Some couples are willing to accept a 1 in 4 chance of having an affected pregnancy. Others choose to conceive naturally and then undergo more conventional invasive prenatal testing such as chorionic villus sampling [16] near 11–14 weeks of pregnancy or amniocen-tesis [17] near 16–22 weeks of pregnancy. These procedures carry an approximately 1 percent risk of pregnancy loss. If a pregnancy is diagnosed as affected by PKU, couples face the option of either terminating the pregnancy or continuing the pregnancy knowing that their child will need lifelong medical management. Preimplantation genetic diagnosis (PGD) is another reproductive option for these couples. Embryos are produced by the in vitro fertilization (IVF) process and are analyzed for the presence of the affected genes. Embryos free of the dis-ease can then be transplanted into the uterus. This reassures couples from the very beginning of a pregnancy that the child will be unaffected by PKU and enables them to avoid invasive prenatal diagnosis [15].
The first successful live birth took place in the United Kingdom following PGD, which detected two mutations in the PAH gene [15]. In general, PGD is more commonly used for diagnosing lethal disorders, and there remains some debate about the appropriate and ethi-cal use of this technology to screen for more chronic, treatable disorders for which effective management is available, such as PKU.
B. Case: Mike and Tanya
Mike and Tanya, who both have normal hearing, are proud parents of a baby boy, Jack. Before they leave the hospital, they are informed that Jack failed the hearing test that was part of newborn screening. Because of this positive screen, they are referred for more detailed and diagnostic hearing tests. When Jack is 3 months old, these tests confirm that Jack has bilateral permanent hearing loss resulting in deafness. Genetic testing reveals two connexin 26 (GJB2) mutations as the cause of Jack’s deafness. At 6 months of age, Jack begins early intervention services and his parents consider pursuing a cochlear implant when he is older.
1. Genetics of Hearing Loss
Profound congenital hearing loss is estimated to occur in about 1 in 1,000 births. Forty percent of cases are thought to be due to environmental factors (e.g., trauma to the ear, drug exposure, bacteria) and 60 percent are thought to be due to genetic causes [18]. Genetic causes can be further broken down into nonsyndromic (the deafness is not associated with other clinical findings that constitute a known syndrome) and syndromic (the hearing loss is associated with a known syndrome). Causes of syndromic hearing loss are extensive and in-clude more than 400 etiologies [8]. More commonly, hearing loss caused by a genetic reason is nonsyndromic. Nonsyndromic hearing loss can be further classified by various inheritance patterns within the family.
When a baby such as Jack is born with deafness to two parents with normal hearing, an autosomal recessive inheritance pattern is suggested. This is the same inheritance pattern as described previously with PKU. Interestingly, mutations within a single gene, GJB2, give rise to more than half of the genetic causes of profound deafness in the United States [8]. As described in the case example, Jack’s deafness was caused by inheriting two GJB2 muta-tions (one from each parent), and thus we also discover that both Mike and Tanya are GJB2
mutation carriers. For each future pregnancy, there is a 25 percent chance that their baby will inherit both GJB2 mutations and be born deaf.
2. Newborn Screening for Hearing Loss
The National Institutes of Health in 1993 recommended that all newborns undergo hearing screening shortly after birth. Numerous professional societies, including the Ameri-can Academy of Pediatrics and ACMG, and the U.S. Preventive Services Task Force followed in supporting this recommendation [8, 19–21]. As of November 2014, newborn hearing screening is required in 35 states, with another nine states offering screening to all newborns [7].
Underlying these recommendations is a consensus that untreated hearing loss can result in lifelong speech and language deficits. Therefore, early identification of hearing loss and prompt follow-up for those who fail the initial screening is critical in fostering
communica-tion development [18]. Newborns who fail the initial screening are referred for more exten-sive hearing loss evaluations and for consultation with a genetic specialist [18].
3. Is Deafness a Disability?
In 2002, the ACMG Genetic Evaluation of Congenital Hearing Loss Expert Panel published a statement on genetics evaluation guidelines for congenital hearing loss [8]. In this statement, the panel asserts that the fundamental goal of well-coordinated newborn screen-ing programs is to reduce mortality, morbidity, and disability in the screened infant [8]. For conditions such as PKU, the benefit of newborn screening seems clear. There is virtually no debate that newborn screening for PKU does indeed reduce mortality, morbidity, and dis-ability in infants with PKU.
Hearing loss, specifically deafness, introduces some shades of gray into the benefit of newborn screening in reducing disability in the screened infant. The ACMG panel’s state-ment cites several studies that provide outcome data showing that early detection of hearing loss, accompanied by the introduction of intervention strategies within the first few months of life, results in an infant’s subsequent development of language skills that approach the skill levels of their peers who do not have a hearing loss [22, 23].
Many deaf people, however, do not consider themselves as having a disability. Instead, many deaf people consider themselves to be part of a distinct cultural group with its own language, customs, and beliefs. Harlan Lane, professor of psychology with expertise in the culture of the “deaf world,” shares his perspective that labeling deafness as a disability “brings with it needless medical and surgical risks for the Deaf child” and “endangers the future of the Deaf-World” [24].
Lane asserts that labeling a deaf child as having a disability places the child at risk for controversial interventions such as cochlear implant surgery. Cochlear implants are small electronic devices that can help provide a sense of sound to a person who is profoundly deaf or severely hard of hearing. The implant consists of a portion that sits behind the ear and another portion that is surgically placed under the skin [25]. The implant does not restore normal hearing but instead can give a deaf person a useful representation of sounds in the en-vironment and help them understand speech [25]. Since 2002, cochlear implants have been FDA approved for use in children beginning at 12 months. As of December 2014, more than 320,000 people have received implants [25].
In 2000, the National Association of the Deaf (NAD) published a position statement on cochlear implants. An excerpt of its statement follows:
The NAD recognizes the rights of parents to make informed choices for their deaf and hard of hearing children, respects their choice to use co-chlear implants and all other assistive devices, and strongly supports the development of the whole child and of language and literacy. Parents have the right to know about and understand the various options avail-able, including all factors that might impact development. While there are some successes with implants, success stories should not be over-gen-eralized to every individual [26].
The position statement also highlights different perspectives on disability between the medical and deaf communities.
Many within the medical profession continue to view deafness essen-tially as a disability and an abnormality and believe that deaf and hard of hearing individuals need to be “fixed” by cochlear implants. This patho-logical view must be challenged and corrected by greater exposure to and interaction with well-adjusted and successful deaf and hard of hearing individuals [26].
These differing perspectives on what constitutes a disability raises some interesting ques-tions about condiques-tions selected to be part of newborn screening and the urgency and proper course of treatment for infants who screen positive for these conditions. It also reinforces the need for culturally sensitive genetic counseling surrounding discussions of disability, prenatal testing, and reproductive technologies related to deafness.
III. Noninvasive Prenatal Screening
A. Case: Altan
Altan is a 37-year-old woman who is 12 weeks pregnant. At her most recent doctor’s appointment, she was offered a new type of screening, called noninvasive prenatal screening (NIPS), in which her blood would be tested to determine whether her baby has a high like-lihood to be born with Down syndrome. Altan’s doctor told her that this testing is routine during pregnancy and, because there is no risk to the baby, it would be a good idea to proceed because she is older than 35. Altan is not sure if she wants prenatal screening for Down syn-drome but agrees to the blood test because her doctor recommended it.
1. The Technology of Noninvasive Prenatal Screening
Prenatal screening for genetic conditions has long focused on identifying pregnancies with the greatest chance of being affected by Down syndrome. Historically, diagnostic testing, such as amniocentesis, was offered to women 35 years of age and older because the chance of Down syndrome affecting a pregnancy increases with maternal age. When the mother is 35 years old, the chance of a fetus having Down syndrome is approximately 0.5 percent; when she is 40, approximately 1 percent; and when she is 45, approximately 3 percent.
Amniocentesis was the first option that was available to test a fetus for Down syndrome. Amniocentesis is an invasive procedure in which a needle is used to withdraw some of the amniotic fluid that surrounds the fetus in order to analyze the chromosomes. Because this procedure is invasive, there is a chance of miscarriage (less than 1 percent). Amniocentesis is a diagnostic test, and diagnostic tests are more accurate than screening tests. Since the development of amniocentesis, other blood-based screening options have become available that screen for Down syndrome and other conditions. These blood-based screening options, however, are not as accurate as the invasive diagnostic options.
NIPS is a screening test that became clinically available in 2011 in which small frag-ments of placental DNA in maternal blood are analyzed. NIPS can be conducted as early as
the 9th or 10th week of pregnancy. NIPS can screen for Down syndrome with no risk to the fetus, with a level of accuracy previously unseen with blood-based screening options.
Down syndrome is caused by having three, instead of two, 21st chromosomes. When a fetus has an extra 21st chromosome, the representation of DNA fragments from the 21st chromosome in the maternal blood is usually higher. Complex statistical analysis determines whether the amount of DNA fragments is significantly higher. If it is, the fetus is highly like-ly, but not certain, to have Down syndrome. In a woman considered high risk [27], a screen positive NIPS result usually indicates there is a greater than 90 percent chance her baby will be born with Down syndrome. It is recommended that all women considering NIPS receive prescreen and postscreen genetic counseling and that positive results be confirmed with diag-nostic testing, such as amniocentesis. This is because NIPS can produce false positive as well as false negative results. The technology behind NIPS is still in its infancy, but it is predicted that one day it will be powerful enough to screen for hundreds of genetic conditions. 2. Prenatal Testing for Down Syndrome
Although other genetic conditions can be identified through prenatal testing, Down syndrome is arguably the most recognizable condition associated with these technologies. Down syndrome is the most common known cause of intellectual disability, and roughly 1 in 700 children are born each year with this condition [28]. More than 400,000 individuals with Down syndrome live in the United States [28]. Down syndrome is a condition char-acterized by mild to severe cognitive impairment, common physical characteristics, and an increased risk for specific health complications. Most individuals with Down syndrome are mainstreamed into schools and live fulfilling lives [28].
Down syndrome is one of the few causes of intellectual disability that is recommended to be routinely screened and tested for during pregnancy, yet it is just one of many genetic conditions that can cause cognitive impairment [4, 29]. Other genetic conditions, such as fragile X syndrome, could be screened for prenatally yet universal screening during pregnancy is not recommended, as it is with Down syndrome [30]. Prenatal screening has focused on the identification of Down syndrome due to a number of factors, including the relatively common frequency of Down syndrome, the fact it is an easy condition to recognize because of the common physical characteristics, and the widespread cultural stereotypes surrounding the condition. When prenatal testing options for Down syndrome were being developed, there was a largely negative societal attitude toward having a child with Down syndrome. According to historian David Wright, research studies conducted in the 1950s–1980s con-cluded that individuals with Down syndrome would negatively impact the family unit and the development of “normal” children [31]. The medical community, the government, and many families often viewed Down syndrome as a preventable tragedy [31].
While Down syndrome has been historically targeted for prenatal testing, societal at-titudes and acceptance have shifted toward greater acceptance of individuals with Down syndrome in the last generation or so. Down syndrome advocacy helped foster a medical community that shifted its views from a largely negative to a more neutral outlook for those with Down syndrome. Even as attitudes toward Down syndrome are changing, the medical recommendation that all women be offered testing for Down syndrome during pregnancy remains.
3. Standardization of Testing for Down Syndrome During Pregnancy
When Altan’s doctor offered her screening for Down syndrome during her pregnancy, the doctor was providing appropriate prenatal care. Prenatal testing (both diagnostic and screening) for Down syndrome has become routine during pregnancy as a result of various social and legal factors. Multiple legal cases helped set the precedent for offering prenatal testing and screening for Down syndrome during pregnancy. For example, the legalization of abortion allowed families to decide whether they wanted to continue or terminate a preg-nancy affected with Down syndrome. After Roe v. Wade, families could decide, to a certain degree, what type of children they were willing to accept. If a woman age 35 or older was not provided the option of amniocentesis or informed of her risks, her obstetrician could be found negligent or families could file wrongful birth lawsuits, as evidenced in the 1970s and 1980s [32–35]. In response to court rulings that a health care provider was negligent if he or she did not offer testing for Down syndrome, ACOG released practice guidelines recommending offering testing for Down syndrome to pregnant women over the age of 35 [36]. Subsequently, ACOG recommended that all pregnant women be offered screening and diagnostic testing for Down syndrome [4] and, even more recently, that NIPS be offered to all pregnant women considered at high risk for having a pregnancy affected with Down syndrome [37].
4. Noninvasive Prenatal Screening and Down Syndrome
Although it is a standard of care to offer prenatal testing for Down syndrome to all preg-nant women, many families find this recommendation concerning. With the introduction of NIPS, noninvasive screening for Down syndrome became significantly more accurate and many families wonder how NIPS will impact Down syndrome. Professional medical group recommendations to offer NIPS to high-risk women may inappropriately promote the idea that testing is always in the best interest of the patient and some women may interpret this to mean that they should undergo testing. Merely offering a test can imply that one should un-dergo testing. One study found that close to half of women did not realize that prenatal screen-ing was optional [38]. Approximately 20 percent of women base their decision to test solely on their doctor’s recommendation [39]. Others may feel stigmatized for declining testing. For example, women are rarely asked their motives for proceeding with prenatal testing, but when they decline, they are often forced to defend their choice [40]. Some parents may feel pressured to proceed with NIPS because it involves only a blood draw. Other families are concerned that the lack of risk may create an environment that fosters less vigorous decisionmaking [41].
With the introduction of NIPS, more fetuses with Down syndrome could be identi-fied. Many pregnancies identified as being affected with Down syndrome end in termina-tion, which begs the question “What does the future of Down syndrome look like?” If more pregnancies affected with Down syndrome are identified and terminated and the condition becomes a medically induced “rare disease,” there is fear that relatively recent advances, such as the acceptance of individuals with Down syndrome and support services, may disappear [42]. Many families and community members value the perspective that individuals with Down syndrome bring to their lives and question what defines “normal” [29]. As one mother stated, “If we try to make everybody the same, we’re going to lose something very basically, fundamentally important to humans” [41].
While there are concerns surrounding the introduction of NIPS into prenatal care, oth-ers believe that NIPS is a welcome option to the Down syndrome diagnostic and screening repertoire. More women who are categorized as high risk are electing to proceed with NIPS, and fewer women are electing to proceed with diagnostic testing [43]. With fewer women undergoing diagnostic testing, fewer pregnancies will be lost to miscarriage unnecessarily. The uptake in NIPS could be due to women who want more accurate information regard-ing Down syndrome — but only if no risk is involved. Perhaps many women and families would have found additional information to be useful but refused to proceed with diagnostic testing because it is associated with miscarriage. This could reflect the desire to be prepared for a child with special needs before delivery, using the time to educate themselves and their families on what it means to have a child with Down syndrome, seek out the local chapter of a Down syndrome advocacy group, identify pediatricians and other specialists who have experience with treating those with Down syndrome, or consider adoption options.
Many groups in society have differing opinions on whether Down syndrome should be a condition tested and screened for during pregnancy. While it is recommended that all women be offered prenatal diagnostic testing and screening for Down syndrome, it is im-portant to note that the recommendation emphasizes choice. In genetic counseling, genetic counselors realize that the “right” choice is going to be different for everyone. But as long as there are prenatal testing options designed to identify pregnancies affected with Down syn-drome and women have the legal option of terminating their pregnancy, there will continue to be friction between disability advocates and the medical model of offering prenatal testing to every woman.
IV. Hereditary Cancers
A. Case: Susan
Susan is a 32-year-old woman with no personal history of cancer. Susan’s mother was diagnosed with cancer in her right breast at age 44 and was later diagnosed with cancer in the left breast at age 59. She died of the disease at the age of 62. Susan is concerned about her breast cancer risk and decides to pursue testing of the BRCA1 and BRCA2 genes. Her test result comes back positive for a mutation in BRCA1, indicating that she has Hereditary Breast and Ovarian Cancer syndrome (HBOC). After consultation with a breast surgeon, she elects to undergo a preventive bilateral mastectomy and plans to have her ovaries surgically removed around the age of 35.
1. Genetics of Hereditary Breast and Ovarian Cancer Syndrome
HBOC is caused by mutations in one of two genes, BRCA1 or BRCA2. It is estimated that approximately 5 to 10 percent of cancers are hereditary, meaning that a mutation in the BRCA1, BRCA2, or other genes is being passed down through the family and is causing cancer in the family. Hereditary cancers include common cancers (e.g., breast cancer) diag-nosed at a young age, rare cancers (e.g., ovarian cancer, male breast cancer) in a family, and cancers diagnosed multiple times in a family (either in the same person or in multiple family members). NCCN publishes updated guidelines annually that contain specific genetic test-ing criteria for hereditary cancers [6].
Women who have mutations in these genes are at significantly higher risk of developing breast and ovarian cancer than those who do not. These women have an up to 87 percent chance of developing breast cancer, compared with approximately 8 percent in the general population, and an up to 44 percent chance of developing ovarian cancer, compared with less than 1 percent in the general population [44–51].
Because of the high risk of developing cancer, cancer screening for this population is vastly different from that for women at average risk. NCCN guidelines currently recommend breast awareness beginning at age 18, clinical breast exams beginning at 25, annual breast magnetic resonance imaging (MRI) studies beginning at age 25, and the addition of annual mammography beginning at age 30 [6]. Even though screening aims to catch breast cancers when they are small and easily treatable, many women such as Susan choose preventive bi-lateral mastectomy (the removal of both breasts) to prevent cancer from developing in the first place. While breast reconstruction after mastectomy is common, the decision to undergo screening or preventive surgery is personal and is influenced by many factors.
Today, no effective screening is available to detect ovarian cancer at an early stage. In ad-dition, signs and symptoms of ovarian cancer are vague and difficult to recognize, resulting in ovarian cancer usually being diagnosed at a later stage. For these reasons, NCCN guidelines recommend surgical removal of the ovaries and fallopian tubes for high-risk women between the ages of 35 and 40 when they are done having children [6].
Although most of the attention regarding BRCA mutations revolves around women, men with BRCA mutations are also at an elevated risk for breast cancer (up to 8 percent) [52, 53] and prostate cancer (up to 20 percent) [54]. NCCN guidelines for men with a BRCA mutation include breast self-exams, clinical breast exams, consideration of mammograms, and earlier prostate cancer screening [6].
One common myth is that BRCA mutations can only be inherited from mothers. The
BRCA genes are inherited in an autosomal dominant manner, which means that they can be inherited from mothers and fathers and passed on to sons and daughters. When a BRCA mu-tation is identified in a person, his or her first-degree relatives (parents, full siblings, children) have a 50 percent chance of having this mutation. Thus, any children Susan has will have a 50 percent chance of carrying her gene mutation. Family members can consider genetic test-ing when they are over the age of 18. Because these mutations run in families, more distant relatives are also at risk of carrying them.
2. “Previvor” Concept
BRCA testing became available in 1996, and since that time, the BRCA genes have become some of the most well-known genes among the general population. Genetic testing has led to the identification of a growing number of BRCA mutation carriers. Several patient organizations have been established to help support the men, women, and families facing hereditary cancer. One patient group, Facing Our Risk of Cancer Empowered, or FORCE, helped coin a new term and concept in preventive medicine: “previvor” [55]. The FORCE website describes this term.
Previvors are individuals who are survivors of a pre-disposition to cancer but who haven’t had the disease. This group includes people who carry a
hereditary mutation, a family history of cancer, or some other predispos-ing factor. The term specifically applies to the portion of our community that has its own unique needs and concerns separate from the general population, but different from those already diagnosed with cancer [55].
FORCE originated the previvor concept in 2000. Since then, the term has been ad-opted by many high-risk women, health care providers, and researchers and was named by
Time magazine as one of its top 10 buzzwords of 2007 [55]. 3. Affordable Care Act and BRCA Testing
Knowing that a man or woman has a BRCA mutation can be lifesaving information, because the cancer management plan appropriate for him or her varies so dramatically from that of the general population. Family members require special screenings to prevent cancer or diagnose it early. A common misconception is that insurance does not cover genetic test-ing. Insurance coverage has improved since BRCA testing was first introduced. Although every insurance company is different, if a patient is tested according to NCCN genetic testing guidelines, the patient pays, on average, less than $100 out of pocket for testing [56].
In 2013, BRCA testing was designated as a preventive care service under the Affordable Care Act, thus acknowledging the importance of genetic testing in personalized preventive medicine. This enables unaffected women (those with no personal history of cancer) but whose family history of cancer meets genetic testing recommendations outlined by the U.S. Preven-tive Task Force to receive BRCA testing with no out-of-pocket cost to the patient [57].
Mary-Claire King, who is credited with localizing the BRCA genes, recently stated, “To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention” [58]. Increased awareness of hereditary cancers and genetic testing among health care profes-sionals and the public is critical to helping families such as Susan’s prevent these cancers.
V. Alzheimer’s Disease
A. Case: Shira
Shira is a 25-year-old woman whose maternal grandmother was diagnosed with Al-zheimer’s disease at age 60 and died from complications related to AlAl-zheimer’s at 65. Her maternal grandmother’s brother was diagnosed with Alzheimer’s disease at age 40 and died from complications from the disease in his late 40s. Shira’s maternal aunt (age 50) is starting to show signs of Alzheimer’s disease and underwent genetic testing that identified a PSEN1
gene mutation. Shira’s mother, who is 48 years old, is currently asymptomatic. Shira is inter-ested in genetic testing for the familial mutation.
1. Brief Genetic Background of Alzheimer’s Disease
Alzheimer’s disease is characterized by progressive, irreversible brain damage that causes memory loss, a loss of global cognitive function, impaired judgment, and can be associated with behavioral and personality changes [59]. In the end stages of this disease, affected in-dividuals are completely dependent on others for fulfilling their basic needs [59]. Approxi-mately 5 million Americans are currently living with Alzheimer’s disease [59]. Age is a risk
factor for developing Alzheimer’s. The risk at age 65 is 3 percent and increases to almost 50 percent in those 85 years and older [60]. Most affected individuals are diagnosed when they are 65 or older (late-onset Alzheimer’s disease), but 1 to 2 percent of individuals receive the diagnosis before age 65 (early-onset Alzheimer’s disease) [61]. As the baby boomer generation continues to age, the number of people affected by Alzheimer’s is expected to increase. Cur-rently, Alzheimer’s cannot be prevented or cured and management options are limited [61]. The majority of individuals with Alzheimer’s disease (approximately 75 percent) are isolated cases in their families [63]. This is called sporadic Alzheimer’s disease. Familial Al-zheimer’s disease is diagnosed when more than one person in a family is affected, which represents about 25 percent of cases [63]. Less than 5 percent of individuals with Alzheimer’s disease present with autosomal dominant inheritance [62], and almost all of these individu-als have early-onset Alzheimer’s disease [63]. Early onset, autosomal dominant Alzheimer’s disease was recently highlighted in the award-winning movie Still Alice.
Only three genes are currently known to be causative for Alzheimer’s disease: PSEN1, PSEN2, and APP. All three genes are associated with autosomal dominant early-onset Al-zheimer’s disease. Of the less than 5 percent of individuals who present with this form of Alzheimer’s and who have a dominant family history, 45 to 90 percent have a causative mutation identified [63]. For the majority of people who develop Alzheimer’s disease, ge-netic testing will not identify a causative gege-netic etiology. This is because the more common sporadic late-onset form of Alzheimer’s disease is thought to be caused by a complex interac-tion between genetic and environmental factors [63]. The genetic factors in these cases are called genetic susceptibility genes. In simple terms, if a person has a causative mutation, he or she will develop the disease, but if a person has a genetic susceptibility, his or her risk for developing the disease increases but it is not guaranteed they will actually develop Alzheimer’s disease. The mutation identified in Shira’s family is a causative mutation, not a susceptibility mutation.
There is a susceptibility gene called APOE, which is associated with Alzheimer’s disease. This gene is thought to be a factor in multifactorial inheritance, in which both genetics and environment play a role in disease development. Some forms of the APOE gene protect against Alzheimer’s disease; other forms are associated with an increased risk for late-onset Alzheimer’s [61]. The usefulness of APOE testing for prediction and diagnosis is controversial [64]. In a joint statement, ACMG and the National Society of Genetic Counselors do not recommend genetic testing for Alzheimer’s susceptibility genes due to limited clinical utility and the lack of meaningful risk calculations necessary for individual counseling [61]. 2. The Right Test for the Right History
As evidenced in the previous case example, family history is a key factor in ordering ap-propriate testing. A three-generation family history is very useful in determining whether an individual’s history is more consistent with sporadic, familial, or autosomal dominant inheri-tance. From Shira’s family history, three factors contributed towards offering genetic testing: (1) early onset of Alzheimer’s disease in multiple family members, (2) the identification of a causative mutation, and (3) the patient’s interest in presymptomatic genetic testing.
Many individuals are familiar with direct-to-consumer testing for Alzheimer’s disease through companies such as 23andMe, which Wilcox and Koff describe in their article in this
issue of NAELA Journal. Direct-to-consumer testing relies on susceptibility genes to provide population-based risk estimates. If Shira were interested in using direct-to-consumer testing to estimate her risk for Alzheimer’s disease, she would need to know that such testing does not test for the genetic mutation in her family. With Shira’s family history, a result based on testing only her susceptibility genes would be completely misleading. Shira’s provider should offer targeted mutation analysis. If she tested positive, Shira will develop Alzheimer’s, and if she tested negative, the chance to develop Alzheimer’s would return to population chances. Even in the absence of a known mutation, a knowledgeable health care provider would coun-sel Shira on the risks associated with an autosomal dominant condition based on the family history alone. Ideally, Shira would be referred to a genetic counselor or specialist who could discuss the benefits and limitations of presymptomatic testing of an adult-onset condition with no cure.
3. Informed Consent
Presymptomatic genetic testing for adult- and late-onset conditions is not exclusive to Alzheimer’s disease and commonly occurs in genetic testing to determine cancer risk (as described earlier in this article). What is unique to Alzheimer’s disease is that genetic testing results do not impact surveillance, treatment, or medical management options in a presymp-tomatic individual. If Shira tests positive for the familial mutation, her provider would only discover that she will develop dementia. Age of onset of Alzheimer’s can span 30 years in the same family; therefore, symptoms could appear in Shira as early as her 30s or as late as her mid-60s. Currently, presymptomatic management and treatments for mutation-positive individuals are extremely limited.
Outside of limited clinical utility, Shira’s results could have implications for other fam-ily members, could affect her own mental health, and could impact her plans for the future. If Shira tests positive, we would know that her mother also carries the mutation and will de-velop Alzheimer’s disease. What if her mother declined genetic testing for Alzheimer’s and did not want to know whether she carried the mutation or would develop the disease? Does Shira have a history of depression or other mental health disorders? If so, how might a positive re-sult impact her current health? Would a positive rere-sult help or hinder her plans for the future?
Presymptomatic testing for conditions without a cure and with no management or treatment options occurs in other areas of genetics. Presymptomatic testing for Hunting-ton’s disease is a classic example of genetic testing for a noncurable, nontreatable condition. Proceeding with presymptomatic testing for Alzheimer’s disease follows the same guidelines that were put in place for Huntington’s disease: The individual’s decision to proceed with testing is made without coercion, the individual is an adult, and the individual undergoes 1) a neurological exam to rule out early stages of dementia, 2) an evaluation by a mental health specialist, and 3) pretest counseling with a qualified provider [60]. Some individuals find these recommendations excessive, but once the test is performed and the results are avail-able, the information cannot be retracted or withheld. Shira’s test results could identify other family members who are carriers; influence her education, career, and reproductive choices; and cause unanticipated emotional and social effects [60]. Shira’s test results could have far-reaching implications on her future regardless of whether the results are positive or negative. For this reason, consent is emphasized before an individual undergoes presymptomatic
test-ing for conditions with limited clinical management options, such as Alzheimer’s disease. Informed consent is also required for Alzheimer’s disease genetic testing of symptomatic individuals. Similar to individuals with Huntington’s disease, it is common for individuals affected by Alzheimer’s disease to be symptomatic by the time genetic testing is offered. If necessary, a surrogate decisionmaker for the Alzheimer’s patient can be identified through an advance directive [60]. Because genetic testing could reveal the genetic status of the patient’s family members, it is critically important for all parties to agree on the testing. Even though genetic testing may not change the person’s treatment or management, genetic knowledge could be useful when better treatment options become available.
If family members disagree about the utility of genetic testing, other alternatives can be explored, such as DNA banking. DNA banking leaves open the option of genetic testing an affected individual’s tissue (usually stored blood) in the future when better genetic tests or treatment options become available. DNA banking also can provide time for families to discuss and decide whether genetic testing for the affected individual is right for the family. 4. Genetic Information Nondiscrimination Act and Insurance
Although genetic information is protected, some individuals still have concerns about proceeding with genetic testing, especially if they are presymptomatic. It is important for individuals considering presymptomatic genetic testing to be aware of the protections and limitations of current genetic antidiscrimination laws. The Genetic Information Nondiscrim-ination Act (GINA), which was passed in 2008, makes it illegal for employers and health insurance providers to discriminate based on an individual’s genetic testing results or family health history. There are, however, important exclusions to GINA [65, 66]. GINA does not protect against genetic discrimination when individuals apply for life, disability, or long-term-care insurance [65, 66]. In addition, GINA excludes discrimination protection in cer-tain health insurance plans, such as the plans offered by small employers (those with fewer than 15 employees) [65, 66].
As Alzheimer’s disease progresses in an individual, appropriate insurance, advance directives, surrogate decisionmakers, and caretakers become increasingly important. Long-term-care insurance covers services and support to assist with activities of daily living such as eating, dressing, and transferring (e.g., walking). Typically, it is best if long-term-care insur-ance is purchased well before Alzheimer’s symptoms appear or genetic testing occurs. Many long-term-care insurance policies have exclusions for Alzheimer’s disease, but if an insurance policy is bought before the manifestation of symptoms, the insurer usually covers the cost of care [67]. Although actual case examples of genetic discrimination involving long-term-care insurance are few and far between, it is nevertheless a concern that if the insurance is not purchased before proceeding with genetic testing, the applicant could be disqualified based on his or her genetic testing results.
VI. Conclusion
The field of genetic testing is rapidly evolving. As technology continues to improve and the cost of genetic testing declines, individuals will likely have access to an incredible amount of genetic information. Although one can only speculate about the technology that will soon become clinically applicable, newborn screening will likely continue to expand as individual
states begin to add more genetic conditions to their screening panels. In addition, NIPS will likely evolve to include more genetic conditions. Genetic testing for cancer susceptibility genes such as BRCA1 and BRCA2 has already expanded, as evidenced by the use of mul-tigene panels (testing for multiple cancer susceptibility genes at one time) to replace single syndrome testing (testing for the BRCA genes only).
These technological advances are accompanied by a growing awareness of genetic test-ing in the general population, both of which make it very likely that Elder Law attorneys will work with clients who have experienced genetic testing and/or genetic conditions in some way. Understanding the uses, benefits, and limitations of genetic testing will help Elder Law attorneys support these clients and will become even more important as the genetic testing field continues to evolve.
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