Genetic Counseling & Alport Syndrome Chelsea Alexander, MS, CGC Genetic Counselor University of Minnesota Medical Center Fairview

Overview Genetic Counseling Genetic Counseling in Alport Syndrome Genetic Testing Examples Genetic counseling – who are we and what do we do?

What is a Genetic Counselor? Health care professionals with specialized graduate degrees and experience in medical genetics and counseling. Enter field from a variety of disciplines, including biology genetics nursing psychology public health social work

Educational Background of a Genetic Counselor Master’s degree in human genetics or a related major Certified by the American Board of Genetic Counseling Qualified to work in a variety of settings: clinics-(majority) commercial labs research labs state health departments pharmaceutical companies etc.

What is genetic counseling?

Family Questions… What is a “genetic condition”? What is genetic testing? What can this testing tell us? What does this result mean? What impact may this have on family members? How do we inform our family?

Genetic counseling is…. Genetic counseling is the process of helping people understand and adapt to the medical, psychological, and familial implications of the genetic contributions to disease. National Society of Genetic Counselors 2006

Role of Genetic Counselors What is the chance of a genetic condition based on family and personal medical history (pedigree)? What are important medical and family concerns? Discuss, coordinate, and interpret genetic tests Educate individuals about genetic conditions Provide counseling/support regarding genetic information (implications for family members) Analyze inheritance patterns and recurrence risks. In a clinical setting…

What else? Provide supportive counseling, especially around time of new diagnosis, pregnancy, etc. Serve as patient advocates (insurance, referrals). Serve as a genetics resource. Research related to medical genetics and genetic counseling. For individuals who have AS and who do not.

Goals of Genetic Counseling For Families and Individuals to: Understand their family history and how it may be related to a condition Discuss and understand the impact of genetic conditions on relatives and the immediate family Participate in decision making about their medical care Provide education that is meaningful for families Discuss genetic testing options and implications Assist with referrals to support groups and other health care providers Genetic testing is not always perfect, and a family needs to know that a negative genetic testing result does not mean that there is not a diagnosis. Provide support in making decisions and coping with genetic conditions Manage associated problems in ways that are best for them and their families

Genetic Counseling in Alport Syndrome? See families at a time of: New Diagnosis: Education, family history, inheritance, testing, resources and support Genetic Testing: Coordinate, review test results and clinical meaning Pregnancy: Partner carrier testing, reproductive options Teens/Young adults: Age appropriate education, reproductive issues, etc Mutations in the COL4A3, COL4A4, and COL4A5 genes cause Alport syndrome. These genes each provide instructions for making one component of a protein called type IV collagen. This protein plays an important role in the kidneys, specifically in structures called glomeruli. Glomeruli are clusters of specialized blood vessels that remove water and waste products from blood and create urine. Mutations in these genes result in abnormalities of the type IV collagen in glomeruli, which prevents the kidneys from properly filtering the blood and allows blood and protein to pass into the urine. Gradual scarring of the kidneys occurs, eventually leading to kidney failure in many people with Alport syndrome. Type IV collagen is also an important component of inner ear structures, particularly the organ of Corti, that transform sound waves into nerve impulses for the brain. Alterations in type IV collagen often result in abnormal inner ear function, which can lead to hearing loss. In the eye, this protein is important for maintaining the shape of the lens and the normal color of the retina. Mutations that disrupt type IV collagen can result in misshapen lenses and an abnormally colored retina. Genetic Testing: For a diagnosis, for carrier testing (identification of X-linked carrier females, as some females may or may not be affected, identification through molecular testing is most accurate), carrier testing for at risk relatives, presymptomatic testing of at risk relatives, possible prenatal diagnosis Genetic Testing: COL4A5 (80% sequencing, 10% deletion) COL4A3/COL4A4 – (~99%, unkown deletion)

Genetic Testing What is it? A type of medical test (usually blood) that attempts to identify changes in chromosomes and/or genes. May be used to attempt to confirm or rule out a suspected genetic condition. Assist in determining a person’s chance of developing or passing on a genetic disorder. Has both benefits and limitations. What do results mean? There are many misconceptions about genetic testing and what it is… Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. , the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing. Many different types – newborn screening, carrier, diagnostic, prenatal, predictive/presymptomatic testing What is direct-to-consumer genetic testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern. (Refer to What is genetic discrimination? for additional information.) Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision. The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result.

Genetic Information Nondiscrimination Act Title I: prohibits health insurers from requesting/requiring genetic information for decisions about coverage, premium rates, or preexisting conditions. Title II: prohibits most employers from using genetic information in decisions of hiring, firing, or terms of employment. Prohibits discrimination in health coverage and employment based on genetic information Act of 2008, May 21st by President Bush (title I – health coverage; title II – employment) Many states have state laws that prohibit genetic discrimination, but degree varies widely There are two exceptions to Title I of GINA: First, health insurers may request genetic information in the case that coverage of a particular claim would only be appropriate if there is a known genetic risk. In the Medicare supplemental policy and individual health insurance markets, genetic information cannot be used as a preexisting condition. Second, in the context of research, when working in collaboration with external research entities health insurers may request (but not require) in writing that an individual undergo a genetic test. The individual may do so voluntarily, but refusal to participate will have no negative effect on his or her premium or enrollment status. The collected genetic information may be used for research purposes only, and not for underwriting decisions. www.genomicslawreport.com/index

What GINA does NOT do… Routine tests that do not examine DNA, RNA or chromosomal changes. Coverage does not extend to: Life insurance Disability insurance Long-term care insurance Not a mandate for coverage of tests. Employment provisions generally do not apply for employers with >15 employees Does not prohibit decisions based on manifestation of disease/disorder. Some Federal Health Services Military – employment not GINA, have Executive Order for federal employees that protects from genetic discrimination GINA Does NOT Apply To members of the United States military, veterans obtaining health care through the Veteran’s Administration individuals using the Indian Health Service, or federal employees enrolled in the Federal Employees Health Benefits program (FEHB).

Example of genetic counseling

Pedigree symbols

Genetics “lingo” DNA- Hereditary material in humans and almost all other organisms in the cell and is capable of self-replication Gene- A hereditary unit consisting of a sequence of DNA that has a specific location on a chromosome and determines a particular characteristic in an organism. Mutation/Gene Change- Change in the DNA sequence. Pedigree- A chart of an individual's ancestors used in human genetics to analyze inheritance of certain traits, especially of familial diseases.

Microhematuria + proteinuria or renal failure Norwegian/Finnish Native American/Irish X-linked inheritance The chance that a child will inherit an X-linked recessive condition in every pregnancy is different for sons and daughters and depends on whether the mother or father has the faulty gene: – When the mother is a carrier of an X-linked recessive faulty gene there is 1 chance in 2 (50%) that a son will be affected by the condition and a 1 chance in 2 that a daughter will be a carrier like the mother – When the father is affected by a condition due to an X-linked recessive faulty gene, none of his sons will be affected but all of his daughters will be carriers of the X-linked recessive faulty gene, although they will generally be unaffected by the condition • Information regarding the appropriateness and availability of testing to determine if a woman is a carrier of an X-linked recessive faulty gene and testing in pregnancy where available and appropriate, can be obtained from the local genetic counselling service If only one male in a family is affected, the likelihood that that individual's mother is a carrier is 85%-90%. Approximately 10%-15% of male probands have XLAS as the result of a de novo mutation. Genetests.org microhematuria Microhematuria + proteinuria or renal failure 5

Microhematuria + proteinuria or renal failure X-linked Recessive Norwegian/Finnish Native American/Irish X-linked inheritance The chance that a child will inherit an X-linked recessive condition in every pregnancy is different for sons and daughters and depends on whether the mother or father has the faulty gene: – When the mother is a carrier of an X-linked recessive faulty gene there is 1 chance in 2 (50%) that a son will be affected by the condition and a 1 chance in 2 that a daughter will be a carrier like the mother – When the father is affected by a condition due to an X-linked recessive faulty gene, none of his sons will be affected but all of his daughters will be carriers of the X-linked recessive faulty gene, although they will generally be unaffected by the condition • Information regarding the appropriateness and availability of testing to determine if a woman is a carrier of an X-linked recessive faulty gene and testing in pregnancy where available and appropriate, can be obtained from the local genetic counselling service If only one male in a family is affected, the likelihood that that individual's mother is a carrier is 85%-90%. Approximately 10%-15% of male probands have XLAS as the result of a de novo mutation. Genetests.org microhematuria Microhematuria + proteinuria or renal failure 19 5

X-linked Inheritance Genes located on the X chromosome Women = two X chromosomes Men = one X chromosome and one Y COL4A5 gene in Alport syndrome: A women can carry a gene change and usually may have hematuria, but some women experience more severe symptoms. Fathers are not expected to pass X-linked traits to their sons. 80% of AS, Xq22, 51 exons -

Women with X-linked Alport syndrome: 1 chance in 2 (50%) that a son will have Alport syndrome 1 chance in 2 (50%) that a daughter will be a carrier like the mother

If the father has X-linked Alport syndrome: All of his daughters will inherit the genetic change (carriers) and may or may not have symptoms. None of his sons would be expected to have Alport syndrome.

Microhematuria + proteinuria or renal failure Norwegian English/Irish In approximately 15 percent of cases, Alport syndrome results from mutations in both copies of the COL4A3 or COL4A4 gene and is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the mutated gene and are called carriers. Some carriers are unaffected and others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria. microhematuria Microhematuria + proteinuria or renal failure 5

Microhematuria + proteinuria or renal failure Autosomal Recessive Norwegian English/Irish In approximately 15 percent of cases, Alport syndrome results from mutations in both copies of the COL4A3 or COL4A4 gene and is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the mutated gene and are called carriers. Some carriers are unaffected and others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria. microhematuria Microhematuria + proteinuria or renal failure 5 24

Autosomal Recessive Recessive inheritance (at conception): 25% chance of having a child with Alport syndrome 50% chance of having a child who is a carrier 25% chance of having a child who does not have Alport syndrome and is not a carrier The parents of a child with Alport syndrome are obligate carriers Approximately 50% of carriers exhibit persistent or intermittent microhematuria. Carriers of ARAS rarely develop proteinuria, hypertension, or renal insufficiency Once sibling is known to be unaffected, the risk of his/her being a carrier is 2/3. Other relatives, extended, such as aunts and uncle could be carriers as well

Microhematuria + proteinuria or renal failure Italian English/Irish 5% of cases AD. People with this form of Alport syndrome have one mutation in either the COL4A3 or COL4A4 gene in each cell. It remains unclear why some individuals with one mutation in the COL4A3 or COL4A4 gene have autosomal dominant Alport syndrome and others have thin basement membrane nephropathy. microhematuria Microhematuria + proteinuria or renal failure 5

Microhematuria + proteinuria or renal failure Autosomal Dominant Italian English/Irish 5% of cases Alport syndrome has autosomal dominant inheritance in about 5 percent of cases. People with this form of Alport syndrome have one mutation in either the COL4A3 or COL4A4 gene in each cell. It remains unclear why some individuals with one mutation in the COL4A3 or COL4A4 gene have autosomal dominant Alport syndrome and others have thin basement membrane nephropathy. microhematuria Microhematuria + proteinuria or renal failure 5 27

Autosomal Dominant 50% chance of having a child with Alport syndrome with each pregnancy Not related to gender Most individuals have an affected parent A proband with an autosomal dominant collagen IV-related nephropathy may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo gene mutations is unknown. Urinalysis is recommended for the evaluation of parents of a proband with an apparent de novo mutation.

Genetic Counseling Services Genetic Counseling at UMMC http://www.uofmmedicalcenter.org/Specialties/GeneticCounseling/S_044824 Minnesota Genetic Counseling Association MNGCA, http://mygenepool.org/ National Society of Genetic Counselors NSGC, http://www.nsgc.org/

References R. Artuso, et al. Advances in alport syndrome diagnosis using next-generation sequencing. Euro J Human Genetics 2012; 20: 50-57. M. Bekheirnia, et al. Genotype-phenotype correlation in X-linked alport syndrome. J. Am Soc Nephrol 2010; 21: 876-883. J. Hertz, et al. Clinical utility gene card for: alport syndrome. Euro J Human Genetics 2012; 20. M. Slajpah, et al. The importance of non-invasive genetic analysis in the initial diagnostics of alport syndrome in young patients. Pediatr Nephro 2005; 20: 1260-1264. Genetests, http://www.ncbi.nlm.nih.gov Genetics Home Reference, “Genetic Testing” http://ghr.nlm.nih.gov/handbook/testing?show=all NIH, http://www.genome.gov/24519851/ National Society of Genetic Counselors, www.nsgc.org