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Healthier World with Quest Diagnostics
37 - Instant insights: Whole exome sequencing for rare disease (8 min)
00:08:21
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welcome to Healthier World with Quest Diagnostics. Our goal is to prompt action from Insight as we keep you up to date on current clinical and diagnostic topics to transform lives and illuminate a path to better health.
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Welcome to a special episode series called Instant Insights, a podcast episode designed to give you quick and highly impactful clinical pearls in just a few minutes. I'm Rebecca Johnson Wheeler, a certified genetic counselor, and today we're going to explore how whole exome sequencing and genetic counselors are helping patients get answers sooner and improve care for patients and families. Navigating Rare Disease Rare disease affects nearly 400 million people worldwide and a significant proportion have a genetic origin. With more than 7,000 rare diseases, many patients face a long and frustrating diagnostic journey, sometimes lasting years. Today, tools like whole exome sequencing, in combination with the expertise of genetic counselors are helping to improve patient care by shortening the path to diagnosis, guiding appropriate test use, and helping patients and providers understand results. Rare disease affects a very small percentage of the population, less than 5 in 10,000 people, but collectively impact more people than all cancers combined with and the largest population affected are children. Historically, multiple sequential genetic tests were used in pursuit of a clinical answer, typically focusing on one symptom at a time. Luckily, advances in genomics and technology over the last few decades have allowed whole exome sequencing to become a first line test. This is shortening the time to diagnosis, but also saving families by preventing potentially unnecessary testing. Clinical practice guidelines from the American College of Medical Genetics and Genomics, the American Academy of Pediatrics, and the National Society of Genetic Counselors all support early exome sequencing in children with unexplained developmental delay, epilepsy or multisystem disease. The whole exome refers to portions of our DNA called exons, the regions that contain the instructions for making proteins. Interestingly, the exons actually only make up about 1 to 2% of our DNA, yet the majority of genetic conditions arise from these regions. Whole exome sequencing is a genetic test that sequences or reads through all of our exons to identify genetic variants or changes in our DNA code that may be explaining the rare disease. I like to think of this like a spellchecker or we know how the gene should be spelled and we're looking for variation to that spelling that could be causing disease. Everyone has variations to how their genes are spelled. It's what makes us unique. Some spelling changes have no impact, like adding the letter U to the word color or favor in the UK or Canada. These don't change the word's meaning, but if you were to change the O to an A, a whole new word is created and the meaning is changed in our genes. When this happens, a letter is inserted, changed or removed. The gene may be read incorrectly and therefore put the individual at risk for disease. The sequencing is completed on DNA extracted from a sample like blood or saliva. Parents can also submit their DNA with their child. This is called trio testing. Often when we're reading through exomes, variants can be identified that have not been seen before or or have limited clinical information. When these uncertain findings arise, having the parent's DNA can help the lab with interpretation. When a new variant is found in the affected person. This is called de novo and is a major cause of rare genetic disorders. This means the variant was not inherited from either parent. Including the parent's DNA increases the diagnostic yield and interpretation of the test. But it's important to note testing can be completed without the parent's DNA or as a duo with just one parent. While the parent's DNA is preferred in some circumstances, other blood relatives may be considered. The results can be classified into three main positive, negative and uncertain. A positive result would indicate that a disease causing or pathogenic variant was identified. These were previously referred to as mutations. Sometimes a pathogenic variant is found in a gene unrelated to the reason testing was ordered. These are often referred to as incidental findings. A negative result would mean no variants were identified. Lastly, a variant of uncertain significance or a VUS indicates there was a variant found. However, it's unclear or the scientific evidence is conflicting whether or not the variant is associated with a higher risk for disease or not. Now let's think about a family with a young child experiencing global developmental delay, speech delay and seizures. While discussing diagnostic testing options, their neurologist mentions whole exome sequencing and the parents decide to move forward with trio testing. The results identify a pathogenic variant in the SLC6A8 gene which is associated with cerebral creatine deficiency disorder. This is a rare X linked disorder that commonly presents with developmental delay, speech and language delay, behavioral differences, seizures, low muscle tone and ataxia. While treatment options may be limited, some symptoms may improve with supplementation with a diagnosis. The family gains an answer and additional information into what the diagnosis means for their child and family. While not every clinically significant variant is accompanied by a medical management guideline, the diagnosis often provides insight for families. Before discussing the results with the family, this provider decides to call 866 GeneInfo at Quest Diagnostics to speak with the genetic counselor about remaining questions. A genetic counselor is a specialized healthcare professional who is trained in helping patients understand their genetic risks, genetic results and next steps, while also playing a key role throughout the testing journey. The Genetic Specific Customer Service Line 866 GeneInfo is available to both patients and providers who may be looking to speak with the laboratory genetic counselor or who have questions about genetic testing. While a full genetic counseling session is not performed, the genetic counselors are available to answer pre and post test questions. In this case, when the provider calls, they ask questions in regards to the inheritance of the gene. The lab genetic counselor reviews while this gene is X linked and the specific finding in the child is de novo, it was not inherited from either parent. The provider asks if the parent's close blood relatives need genetic testing at this time, which the genetic counselor confirms they do not. At the conclusion of the call, the provider plans to refer the parents to a clinical genetic counselor and geneticist to discuss medical management guidance and future family planning. Whole exome sequencing offers a powerful way to move beyond the traditional stepwise testing approach and instead evaluate many potential genetic causes at once, particularly in those patients with complex presentations. By reducing the diagnostic odyssey, exome sequencing can help connect patients and families to answers sooner, for more personalized care and management, and provide clarity that can guide both current treatment decisions and future planning. In the rapidly evolving space of genetic testing, Quest Diagnostics is bringing together cutting edge technology and with expert genetic counseling to help patients, families and providers navigate genetics with confidence. As a full service laboratory, we support the genetics continuum of care, meeting today's needs while advancing what's possible for tomorrow.
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That's a wrap on this episode of Healthier World with Quest Diagnostics. Please follow us on your favorite podcast app and be sure to check out Quest Diagnostics Clinical Education center for more resources, including education, educational webinars and research publications. Thank you for joining us today as we work to create a healthier world, one life at a time.