Genomic sequencing is the diagnostic test of choice for families with undiagnosed or rare diseases seeking an explanation for their child’s complex medical concerns. The desire to find answers can easily bias interpretation of sequencing results, and thus the counseling process is designed to facilitate informed decision making and set realistic expectations for possible outcomes. The patient case examples serve to highlight the various challenges and complexities encountered with the clinical application of genomic sequencing and to reflect some of the data that has been accrued during the past 5 years of clinical experience.
Key points
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Genomic sequencing is the diagnostic test of choice for families with undiagnosed or rare diseases seeking an explanation for their child’s complex medical concerns.
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The concept of sequencing all of the known genes and grasping the enormity of the data generated within this process is challenging to comprehend for most physicians, let alone patients and families who have been struggling with a life-altering disease.
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The desire to find answers can easily bias interpretation of sequencing results, and thus the counseling process is designated to facilitate informed decision making and clearly set realistic expectations for possible outcomes.
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The patient case examples serve to highlight the various challenges and complexities encountered with the clinical application of genomic sequencing and to reflect some of the data that have been accrued during the past 5 years of clinical experience.
The odyssey
To end the odyssey, one must first understand the journey. This term diagnostic odyssey is used freely in the lay press and has been the subject of several recent publications in the scientific literature. Is the odyssey the legions of investigations undertaken by the health care providers in an attempt to define and diagnose the cause of the symptoms that brought the patient to medical attention? Is it the frustration of the person impacted and his or her family with the seeming futility of modern medicine, or the doctor shopping in an attempt to identify a provider who is able to listen and compute that the myriad of seemingly disparate symptoms are connected in some way? These encompass any individual odyssey that ends, not necessarily in treatment, but in defining the underlying cause. The average time taken to reach a diagnosis in a rare disease (typically defined as a disorder affecting <1 person in 2000) is 6 years, requiring multiple visits to health care providers.
The advent of massively parallel sequencing has enabled genomic sequencing technologies to be used to identify rare and previously undiagnosed diseases and is a real game changer for modern diagnostics. This article explores the process of how patients initially engage with this technology and how the outcomes impact their ongoing ability to cope with illness and disease and explore the range of feelings and reactions that may arise.
The odyssey
To end the odyssey, one must first understand the journey. This term diagnostic odyssey is used freely in the lay press and has been the subject of several recent publications in the scientific literature. Is the odyssey the legions of investigations undertaken by the health care providers in an attempt to define and diagnose the cause of the symptoms that brought the patient to medical attention? Is it the frustration of the person impacted and his or her family with the seeming futility of modern medicine, or the doctor shopping in an attempt to identify a provider who is able to listen and compute that the myriad of seemingly disparate symptoms are connected in some way? These encompass any individual odyssey that ends, not necessarily in treatment, but in defining the underlying cause. The average time taken to reach a diagnosis in a rare disease (typically defined as a disorder affecting <1 person in 2000) is 6 years, requiring multiple visits to health care providers.
The advent of massively parallel sequencing has enabled genomic sequencing technologies to be used to identify rare and previously undiagnosed diseases and is a real game changer for modern diagnostics. This article explores the process of how patients initially engage with this technology and how the outcomes impact their ongoing ability to cope with illness and disease and explore the range of feelings and reactions that may arise.
Genetic counseling
Genetic counseling is the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease”. Families with undiagnosed or rare diseases are often on a diagnostic odyssey seeking an explanation for their child’s illness. For these patients, genomic sequencing, either whole-exome sequencing (WES) or whole-genome sequencing (WGS), is the diagnostic test of choice. Currently the majority of genomic sequencing relates to WES, and further discussion will focus on this technology. Genetic counseling is warranted in these cases to facilitate informed consent, discuss key parental concerns, and explore the patient/family experience surrounding the consent process and results disclosure for WES.
Identifying realistic expectations of WES is a critical part of obtaining informed consent. There is often a misunderstanding that if all the genes are sequenced, the answer to the ailments will be revealed. However, WES may only provide such an answer in a quarter to a third of analyses despite most all participants hoping that it is the final step in their diagnostic journey. Genetic counseling for WES requires educating the patient or family about the test and implications, as well as working with families to facilitate informed decision making. This process can be cognitively and emotionally taxing. Families are presented with complex possibilities, predictions, and uncertainty and asked to make sophisticated comparisons between the benefits and limitations of testing.
Uncertainty or limitations of medical and scientific information, the clinical utility of treatment or preventative care, and even consideration of trade-off between risk and benefit are key elements of discussion during the counseling for consideration of clinical WES testing. Given that all individuals interpret and react to uncertainty differently, how the individual patient/family deals with stress and coping must be taken into consideration. Uncertainty may differ for each family. For many families, this may include clinical symptoms the patient experienced, the treatment decisions at hand, and concern for the health of additional family members. It also includes the potential of a molecular diagnosis, lack of a molecular diagnosis, and the likelihood of finding an undesired or uncertain molecular result.
There are some common questions and concerns that may arise during informed consent for WES, including the chance of the test providing a diagnosis, privacy and confidentiality of the test result(s) and data, impact on other family members, the anticipated response to results, insurance discrimination, and the impact of results on the patient’s medical management. Common misperceptions include that a negative result excludes a genetic diagnosis, that the laboratory report will include numerous secondary or incidental findings, and that the test will provide a diagnosis. Patients and families who have elected to know incidental findings from WES often express disappointment when the report is negative.
Results from WES are classified into 2 main categories: primary results and secondary results or incidental findings. Testing can yield positive or negative results, or variants of uncertain significance. Primary results are likely pathogenic changes felt to be responsible for the phenotype investigated. Secondary results are likely unrelated to the phenotype under investigation, felt to cause disease/risk, or greatly modify risk for disease.
A categorical model for results disclosure ( Figs. 1 and 2 ) is used to establish a cognitive framework for patients/parents, who have the option to choose the results that they would like to receive based on category:
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Primary result: likely pathogenic DNA variants felt to be responsible for the phenotype investigated
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Secondary result: DNA variants likely unrelated to the phenotype under investigation
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Medically actionable: variant in a gene where knowledge of the particular variant will affect medical decision making such as initiation of a treatment
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Not medically actionable: variant(s) that increase an individual’s risk for disease where no treatment is proven to significantly change medical decision making
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