Pathway‘s drug response panel includes aminoglycoside antibiotics and risk of hearing loss.  This phenotype may be of particular interest to couples planning a pregnancy.

The 1555 mutation and risk of antibiotic-induced hearing loss

For more than 60 years, aminoglycoside antibiotics such as streptomycin, gentamicin, neomycin, paromomycin, kanamycin, amikacin, netilmicin and tobramycin have been widely used, and continue to be used, especially in developing countries, for the treatment of severe bacterial infections. However, aminoglycoside use also carries the risk of hearing loss (also known as ototoxicity).

Pathway tests for a mtDNA mutation, called 1555A>G, which is the most frequent cause of inherited aminoglycoside-induced ototoxicity. The “1555 mutation” occurs in all ethnic groups and has been found to occur in approximately 1 of every 500 people of European descent (PMID 19196684, PMID 19196685). Newborn screening for the 1555 mutation has been suggested in China, where aminoglycoside antibiotics are more commonly used (PMID 21324532, PMID 21329993).

Pathway screens for a mutation in mtDNA, called 1555A>G, which is the most frequent cause of inherited aminoglycoside-induced hearing loss.

There are other mutations that are associated with antibiotic-induced hearing loss, but the 1555 mutation is the most prevalent. Carriers of the 1555 mtDNA mutation who undergo even a single course of aminoglycoside antibiotic therapy can suffer a severe and irreversible loss of hearing (PMID 20301595).

There is no report of a 1555 mutation carrier receiving aminoglycosides and not suffering a significant loss of hearing.

For individuals that carry the 1555 mutation, the recommended action is simple. Avoid aminoglycoside antibiotics. There are many alternatives to aminoglycoside antibiotics, and your physician can decide which is best for you.

There is no report of a 1555 mutation carrier receiving aminoglycosides and not suffering a significant loss of hearing.

However, individuals who carry the 1555 mutation and avoid aminoglycoside antibiotics are still at some risk of hearing loss.A few 1555A>G carriers who were not exposed to aminoglycoside antibiotics have developed hearing loss, suggesting that there might also be other environmental or genetic “triggers” that cause hearing loss in carriers (PMID 20301595).

Why is the 1555 mutation important for prospective mothers?

If you are female and pregnant or planning a pregnancy, we encourage you to be tested for this mutation. If you are female and your test results show that you carry the 1555 mutation, your child is likely to inherit the mutation.

In the US, aminoglycoside antibiotics are often prescribed in the neonatal intensive care unit to treat newborns with bacterial infections (PMID 15846011). For a newborn that carries the 1555 mutation, the risk of hearing loss can be avoided, simply by prescribing a different type of antibiotic (PMID 19192037).

Male carriers, on the other hand, will not pass the 1555 mutation on to their children. The 1555 mutation is mitochondrial and thus is transmitted maternally.

How does the 1555 mutation and aminoglycoside use cause hearing loss?

Aminoglycoside antibiotics wield their antibacterial effects by binding to bacterial ribosomes, the protein making machinery in cells, and thus disrupting protein synthesis in the bacteria.  Even though these antibiotics are usually administered so that all the cells in the body are exposed, they tend to accumulate in the fluids of the inner ear (PMID 3044302).

The 1555 mutation occurs in a molecule that is part of the mitochondrial ribosomes in the hair cells of the inner ear – these are the cells that sense sound vibrations, and allow you to hear. The 1555 mutation permits aminoglycoside antibiotics to bind to hair cell mitochondrial ribosomes, where they disrupt protein synthesis (PMID 19687236, PMID 18308926). The disruption in protein synthesis leads to the death of the hair cells in the inner ear, and eventually, irreversible hearing loss.

Genetic testing can help you or your child avoid hearing loss

Testing for the 1555 mutation is not currently part of any standard newborn or fetal screening test.  Pathway’s test for the 1555 mutation can give you actionable information about your risk of aminoglycoside-induced hearing loss. If you are female, testing for the 1555 mutation can also give you information about your child’s risk of aminoglycoside-induced hearing loss.

Cystic fibrosis

Gunnar Esiason, who has cystic fibrosis and is now a freshman at Boston College, with his famous football dad, Boomer. Image from Boston Globe Staff, Essdras M Suarez

Seventeen years ago, at 2 years old, Gunnar Esiason, the son of Boomer Esiason, NFL sportcaster and former Cincinnati Bengals quarterback, was diagnosed with cystic fibrosis. Shortly after his son’s diagnosis, Boomer founded the Boomer Esiason Foundation, a charity devoted to funding research for a cure for cystic fibrosis. Dramatically increasing the public awareness of cystic fibrosis, the foundation is also committed to further heightening public awareness of the condition, as well as educating and improving the quality of life for those who live with the disease.

Affecting over 70,000 people across the globe, cystic fibrosis is the most common genetic disease in Caucasians, and is caused by defects in the CFTR gene, which codes for a protein that transports electrolytes across cell membranes. Defects in the CFTR affect a person’s body in many ways, including the production of thick mucus in the lungs, blockage of digestive enzyme release in the pancreas, and blockage of sperm passage in the vas deferens. These physiological problems lead to the clinical symptoms of cystic fibrosis, which include chronic pulmonary disease, inflammation of the lower airways, gastrointestinal abnormalities, salt-loss syndromes, as well as infertility in males.

While there is currently no cure for cystic fibrosis, and death from complications of this condition is usually due to respiratory failure, prompt treatment to keep the lungs clear of thick mucus and to ensure adequate nutritional intake can help those with cystic fibrosis lead healthier and more productive lives. With such treatment, the average life expectancy of individuals with cystic fibrosis has increased to 37 years.

Pathway screens for more than 80 mutations in the CFTR gene, including all 23 mutations recommended for screening by the American College of Medical Genetics (ACMG) and by the American College of Obstetricians and Gynecologists (ACOG). Our screening includes the most recurrent mutation, known as deltaF508, which comprises up to 70 percent of cystic fibrosis mutations found in some populations, and is by far the most common CFTR mutation in the world. The availability of genetic screening for cystic fibrosis mutations, since the discovery of the CFTR gene in 1989, has resulted in a decreased incidence of the disease in several populations.

In Caucasians and Ashkenazi Jews, up to 1 in 25 people are carriers of a cystic fibrosis mutation. For Hispanics, African Americans and Asian Americans, 1 in 58, 1 in 61 and 1 in 94 people, respectively, are carriers of a cystic fibrosis mutation.

Homocystinuria, classic type

The characteristic physical features of individuals who suffer from the genetic disease called classic type homocystinuria have led researchers to speculate that the Egyptian Pharaoh Akhenaten, who became king in 1364 BC, suffered from homocystinuria. Since its discovery in 1962, classic type homocystinuria has become one of the state-mandated inborn errors of metabolism for which newborn infants are screened.

Classic type homocystinuria is a devastating disease in which affected individuals cannot break down particular amino acids (homocysteine and methionine) in the food they eat. These individuals have defects in the CBS gene, which codes for an enzyme called cystathionine beta-synthase. Newborns with homocystinuria usually do not have symptoms, and without newborn screening, the disease is often not diagnosed until after the age of 2 years. The first symptom is usually dislocation of the lens of the eyes. Other clinical symptoms may include skeletal abnormalities, such as scoliosis and long, thin arms and legs that give patients a Marfan-like appearance, as well as significantly impaired cognitive functioning, developmental delay and blood clotting problems.

If untreated, individuals with homocystinuria die at an earlier age than normal, usually from stroke or heart disease. However, if detected early, homocystinuria is treatable with a special diet and vitamin supplements.

Pathway screens for the three most common mutations in the CBS gene which cause classic type homocystinuria as well for more than 40 less common CBS mutations.

Classic type homocystinuria is a rare disease so the carrier rate is not known. However, the worldwide incidence of the disease is estimated to be approximately 1 in 200,000 to 1 in 300,000 babies (with two copies of the bad gene). In some populations, the incidence is higher, with rates as high as 1 in 20,000 to 1 in 60,000 babies in Irish, German, Dutch and Australian populations. In comparison, consider that the incidence of cystic fibrosis is 1 in 2,500 to 3,000 babies (with two copies of the bad gene) in Caucasians.

How can extended carrier screening help?

Both cystic fibrosis and classic type homocystinuria are inherited in an autosomal recessive fashion. Each person has two copies of a gene, one from each parent, and both must be altered or mutated for a recessive disease to develop. People who are carriers have one good copy and one bad copy of the gene. Carriers are usually not affected and do not show any symptoms. If both parents are carriers, there is a 25 percent chance each child could inherit two copies of the bad gene and develop the disease.

For prospective parents, Pathway’s Extended Carrier Status Screening can tell them whether they are likely to carry one of the mutations that cause cystic fibrosis or classic type homocystinuria. If both prospective parents are positive for mutations in the same disease gene, their child can be screened for the disease as soon as he or she is born. If the child has the disease, treatment can begin immediately, and symptoms can be prevented. In some cases, parents choose assisted reproductive methods when a risk of a devastating disease is known, for example, people may elect to use preimplantation genetic diagnosis (PGD), egg or sperm donors, or other surrogacy methods to ensure that their child does not have the disease.

For more information about Pathway’s Extended Carrier Status Screening service, or our other services, please contact a Pathway representative at (877) 505-7374 or feedback@pathway.com.

What is carrier screening?

Pathway’s Extended Carrier Status Screening service examines prospective parents for 76 recessive genetic diseases. This newly extended service is available to physicians and their patients.

It is important for prospective parents to be equipped with critical information regarding their own genetics when considering conception.

Although recessive disorders are rare, they become very real when a family has a child unexpectedly born with two disease-causing recessive mutations. Most of our genes are present in two copies because we inherit one copy from each parent. Recessive inherited diseases are those which show no symptoms unless both copies of a gene, one from the mother and one from the father, are altered or mutated in the child. A carrier is a person who has only one copy of a disease-causing mutation for a recessive inherited disease, is not affected, and does not show symptoms of the condition. This means that both prospective parents could be carriers and not know it. Moreover, if both parents are found to be carriers of mutations that cause the same disease, their child may be at risk of developing that disease.  Some of these diseases are easily treated if diagnosed early. Other conditions, however, are devastating.

Why is carrier screening needed?
Traditionally, pregnancy-related genetic testing has been limited to prospective parents whose family history or ethnicity suggests that they may be at an increased risk for a particular genetic disease. One example of this is genetic screening for Tay-Sachs disease mutations in people of Ashkenazi Jewish origin. The problem with this approach is that it relies on self-reported ethnicity and family history, which can be incomplete or misleading. Additionally, the ethnic distribution and prevalence of many genetic disease-causing mutations is not known.

The Simple Solution
Using only a saliva sample, advancements in science, medicine and laboratory technology now make it possible to detect an exceptional number of these recessive mutations in prospective parents. To provide the most complete report possible, we recommend that both prospective parents are tested at the same time.

Accurate and Safe Analysis
Our on-staff geneticists and physicians crosscheck and validate the information in each report before the genetic results are delivered to the ordering physician. All samples go through rigorous analysis and quality control, and Pathway’s reports reflect the best available genetic evidence. We use custom disease-targeted genotyping technologies that are capable of testing for the presence of thousands of mutations in a person’s DNA. Analysis of genetic testing results is accomplished by our highly trained staff and is relayed back to the physician and patient securely and privately in a comprehensive, self-explanatory report. Our privacy and security program protects an individual’s saliva sample, DNA extract, genetic testing and report results, as well as any other personally identifiable information.

Genetic Counseling
We are devoted to making our testing process and reporting as simple as possible; however, we understand that, for some people, testing one’s genetic makeup can be a daunting experience. It is our goal to make the testing process as worry-free as possible. One of the ways we do this is by offering physicians and their patients a free genetic counseling service, which is fully staffed by qualified counselors who are Board-eligible/certified by the American Board of Genetic Counseling. All our genetic counselors are under the supervision of our on-staff medical doctors.

Summary
Because the reports we provide are meant to be educational and informative, the practical information within the reports provides prospective parents with a foundation to begin, or continue, a conversation with their medical providers. The information in the report is not meant to frighten or intimidate people into making hasty decisions, but rather to strengthen the patient-physician relationship through the availability of genetic information. Moreover, extended genetic carrier status testing practically informs and educates prospective parents about the possibility of passing on a recessive genetic condition to their children. By providing physicians with another tool to help personalize the delivery of care while educating patients about their risks, extended genetic carrier status testing holds the promise of providing better, more comprehensive and personalized healthcare at an affordable price. For more information about Pathway’s Extended Carrier Status Screening service, or our other services, please contact a Pathway representative at (877) 505-7374 or feedback@pathway.com.

THE STEPS

For Patients

Step 1: First, ask your doctor about Pathway Genomics’ personal genetic reports. In addition, you can easily notify your physician of your interest in Pathway’s services, by visiting www.pathway.com/physicians/notify and simply filling in the blanks!
Step 2: Using Pathway’s Saliva Collection Kit, you provide a small amount of saliva. Your physician will mail your saliva sample to Pathway Genomics, along with the ordering information.
Step 3: You will need to go online to provide profile information, consent to the testing, and pay any laboratory processing fees.
Step 4: Wait for instructions from your doctor.

For Physicians

Step 1: First, you should meet and discuss Pathway’s services with your patient.
Step 2: Next, you will need to contact Pathway Genomics to arrange for a Saliva Collection Kit to be sent to your office.
Step 3: Then, using Pathway’s Saliva Collection Kit, arrange to collect a saliva sample from your patient.
Step 4: Lastly, simply complete and fax the physician order form to Pathway.

Dr. Eric Topol is the Director of the Scripps Translational Science Institute in La Jolla, California.

“Eric Topol, the cardiologist who helped establish the effectiveness of several important blood thinners and who raised early concerns about the risks of the arthritis drug Vioxx, has a wonderful piece in the current issue of Science Translational Medicine, a research journal, speculating about how new genetic technologies could enter the health care system.” Click here to read more…

“We are all biologically unique, even those of us who have an ‘identical’ twin. The way we respond to a medication varies considerably, from being unresponsive, hyper-responsive, or developing serious side effects.” Click here to read more…

We want the public, FDA and Congress to know that Pathway is not a direct-to-consumer (DTC) genetic testing company. We define DTC as allowing a customer to order and receive test results without the involvement of a licensed physician. New technologies have enabled expert physicians to facilitate this in ways that differ from a traditional physician-patient relationship, and we feel that this is an important trend in facilitating patient access to expert providers, lowering costs, as well as addressing some privacy concerns. Nevertheless, even though Pathway has always had expert physician and genetic counselor review and oversight over the ordering and delivery of our genetic testing services, Pathway voluntarily suspended the ability for customers to purchase a collection kit at our website or any retail outlets.

Furthermore, the GAO report released at the congressional hearing investigated 15 companies and identified some practices of DTC genetic testing companies that should not be tolerated and have no place within the scientific and medical community. As acknowledged during the hearing, none of the companies that testified engage in those practices, and only one of the other twelve was identified. As a result, media coverage following the hearing focused on Pathway Genomics, Navigenics, and 23andme, and it unfairly associated the scientific leaders of this emerging industry with what the GAO referred to as “bottom feeders” who are exploiting people’s misunderstanding of genetic tests.

We would be remiss if we did not recognize that the GAO report highlights some legitimate concerns that are relevant to Pathway. During the hearing, an audio clip was played that implied that one of Pathway’s genetic counselors encouraged a woman to submit her fiancé’s saliva sample in order to surprise him with a genetic report. It is important to know that the caller was talking to a customer service representative, and not a genetic counselor. Regardless, this occurrence was brought to the attention of our management team immediately after it happened, and long before we knew it was part of a GAO investigation. We addressed the issue with the customer service team to make it clear that we do not accept samples to be submitted on behalf of someone else. Furthermore, we require personal consent for every sample.

Moreover, the GAO highlighted different interpretations in risk of outcomes reported by the GAO. We appreciate how one concludes from this that these tests are unreliable, but it is important to recognize that only applies to the health conditions report, not carrier status or drug response and that this report provides an estimate of risk, not a diagnosis of disease or prediction.   Differences in interpretation of test results are not uncommon in medical care. This is why second opinions are often requested by patients, and it is why doctors differ in their opinions on how to guide patient treatment. It is for these reasons that we encourage our customers to use this information as one additional piece of information to be used in making health decisions, as an enhancement to and not a replacement for other risks including environment, lifestyle and family history. Pathway, 23andme and Navigenics all apply different rules for which genetic markers to use and which research paper to reference for odds ratio calculations, but that does not make them incorrect. To help offer transparency into how Pathway calculates results, we are developing a new web page laying out our processes for scientific curation, the criteria that we use in selecting research publications and the methods that we use to calculate risk for the health conditions report. Additionally, we support the common conclusion that regulatory bodies and industry need to agree on standards, and look forward to an ongoing dialogue with FDA and others to define those.

Moving forward, if this past week highlighted one thing for us it is that genetics and genetic information is significantly misunderstood. Some of this is because our knowledge is swayed by science fiction, popular movies and television shows that portray extreme scenarios, often emphasized for their entertainment value over their scientific credibility. Further, the field of genetics is broad, and it covers a variety of testing. The discussions about legitimate issues and concerns need to be focused more specifically to the types of testing and procedures being analyzed. The issues and concerns surrounding genetic risks for complex, adult-onset health conditions are very different from those surrounding carrier status testing, drug response testing, or other forms of testing. Given the complexity of these issues, in-depth objective analyses and discussion often do not occur, intensifying the potential for misconceptions.

As a leader in this emerging industry, Pathway Genomics does not seek to hide behind these realities or use them to brush off legitimate concerns. We believe that genetic testing holds the promise of fundamentally shifting the delivery of health care, allowing for more personalized treatment and proactive prevention of disease. While our understanding of genetics is still growing, it is no reason to postpone taking advantage of the best information we have today. To that end, this post marks the beginning of a multi-series project being initiated by Pathway to educate physicians, patients, policy makers, and anyone else interested in a greater understanding of the emerging field of genetics. This series will aim to be objective and informative, and will focus on a single topic at a time, allowing us to provide the depth and focus that are needed to establish a fair understanding of this industry, its promise and its risks. Our first post, which will be available here next week, will provide an in-depth explanation of why different genetic testing companies can produce different estimates of risk for complex health conditions.

One of the studies, led by Dr. Mark Sager, director of the Wisconsin Alzheimer’s Institute and professor of medicine at the University of Wisconsin School of Medicine and Public Health, included 726 middle-aged and healthy individuals carrying the TOMM40 gene and with a family history of Alzheimer’s disease. According to the university’s website, “Researchers discovered that the 229 people with the high-risk version of TOMM40 did significantly worse on tests of learning and memory than study participants with the low-risk version.”

The second study was led by University of Wisconsin School of Medicine professor and Madison VA Hospital Geriatric Research of Education and Clinical Center researcher, Dr. Sterling Johnson. The data Johnson analyzed concluded “that healthy, middle-aged adults who have the high-risk version of TOMM40 had a significantly lower volume of gray matter in two brain regions affected in early Alzheimer’s disease.”

“This is the first study to associate TOMM40 to brain imaging in people at risk for Alzheimer’s,” said Johnson. “The research suggests that the group with the high-risk version of TOMM40 may be having early signs of cognitive and brain changes related to Alzheimer’s.”

This discovery in genetics and its connection with Alzheimer’s disease comes to the scientific and medical community on the heels of such revelatory studies as Boston University School of Medicine’s Risk Evaluation and Education for Alzheimer’s disease (REVEAL) study. The 2009 study concluded that, in general, there are not significant long-term risks, such as anxiety or depression, associated with receiving genetic test results. Researchers found that asymptomatic first-degree relatives of Alzheimer’s patients who received genetic testing results regarding a possible propensity for Alzheimer’s disease (the presence of an APOE ε4 allele) did not have a change in the levels of anxiety, depression or overall general distress. According to the study, “The disclosure of APOE genotyping results to adult children of patients with Alzheimer’s disease did not result in significant short-term psychological risks.”

Click here to read more about the studies led by Dr. Mark Sager and Dr. Sterling Johnson.

Click here to download the full text of Boston University School of Medicine’s REVEAL study (PDF).