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The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.
To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing
When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.
“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”
One reason for late diagnosis is the need for more knowledge or familiarity a clinician may have with a certain disease, given its rarity.
Perhaps the nebulous nature of genetic testing for people living with rare diseases unveils another drawback, which centers around what researchers refer to as the “diagnostic odyssey.” While the concept describing the average time to diagnosis as 5 years, the time to diagnosis can vary greatly in the rare disease community. In some cases, patients may experience diagnostic delays of only a few months. For others, the time frame could be a decade or greater. The time frame often depends on the patient’s age, phenotype, and accessibility to resources.
Despite these diagnostic challenges, Debra Regier, MD, PhD, chief, genetics and metabolism, at Children’s National Hospital in Washington, DC, sees the silver lining in identifying the underlying cause of a patient’s symptoms of illness. In some cases, a diagnosis leads a patient to access disease-specific medication. However, in the rare genetic disease space, the occurrence is low, as only approximately 10% of these diagnosed conditions have an available treatment.
Despite the small selection of disease-specific therapies for this patient population, patients may still have options, especially when it comes to palliating symptoms.
“We often look toward disease experts to consider what medications are more likely to be supportive,” Dr. Regier said. “This might mean considering a pain regimen, a seizure regimen, other type of symptomatic treatment, or even using some information learned to support the current patient from cases where other families may have preceded them in the odyssey.”
Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea
Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.
One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.
Unfortunately, the drawbacks do not stop there.
“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”
Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress
Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.
In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.
Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.
“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”
Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
Establishing Social Support Networks Typically Falls on the Patient and Loved Ones
Another con in rare genetic diseases is the lack of adoption across the community.
Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.
Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases
As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.
In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.
Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”
As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.
Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.
Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.
“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
Accessibility and Lack of Geneticists Often a Rate-Limiting Step
The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”
Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.
Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.
In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity
Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”
Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family — and patient — is different.
“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”
Suggested Reading
Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.
Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.
The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.
To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing
When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.
“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”
One reason for late diagnosis is the need for more knowledge or familiarity a clinician may have with a certain disease, given its rarity.
Perhaps the nebulous nature of genetic testing for people living with rare diseases unveils another drawback, which centers around what researchers refer to as the “diagnostic odyssey.” While the concept describing the average time to diagnosis as 5 years, the time to diagnosis can vary greatly in the rare disease community. In some cases, patients may experience diagnostic delays of only a few months. For others, the time frame could be a decade or greater. The time frame often depends on the patient’s age, phenotype, and accessibility to resources.
Despite these diagnostic challenges, Debra Regier, MD, PhD, chief, genetics and metabolism, at Children’s National Hospital in Washington, DC, sees the silver lining in identifying the underlying cause of a patient’s symptoms of illness. In some cases, a diagnosis leads a patient to access disease-specific medication. However, in the rare genetic disease space, the occurrence is low, as only approximately 10% of these diagnosed conditions have an available treatment.
Despite the small selection of disease-specific therapies for this patient population, patients may still have options, especially when it comes to palliating symptoms.
“We often look toward disease experts to consider what medications are more likely to be supportive,” Dr. Regier said. “This might mean considering a pain regimen, a seizure regimen, other type of symptomatic treatment, or even using some information learned to support the current patient from cases where other families may have preceded them in the odyssey.”
Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea
Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.
One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.
Unfortunately, the drawbacks do not stop there.
“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”
Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress
Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.
In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.
Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.
“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”
Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
Establishing Social Support Networks Typically Falls on the Patient and Loved Ones
Another con in rare genetic diseases is the lack of adoption across the community.
Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.
Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases
As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.
In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.
Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”
As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.
Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.
Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.
“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
Accessibility and Lack of Geneticists Often a Rate-Limiting Step
The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”
Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.
Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.
In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity
Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”
Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family — and patient — is different.
“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”
Suggested Reading
Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.
Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.
The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.
To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing
When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.
“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”
One reason for late diagnosis is the need for more knowledge or familiarity a clinician may have with a certain disease, given its rarity.
Perhaps the nebulous nature of genetic testing for people living with rare diseases unveils another drawback, which centers around what researchers refer to as the “diagnostic odyssey.” While the concept describing the average time to diagnosis as 5 years, the time to diagnosis can vary greatly in the rare disease community. In some cases, patients may experience diagnostic delays of only a few months. For others, the time frame could be a decade or greater. The time frame often depends on the patient’s age, phenotype, and accessibility to resources.
Despite these diagnostic challenges, Debra Regier, MD, PhD, chief, genetics and metabolism, at Children’s National Hospital in Washington, DC, sees the silver lining in identifying the underlying cause of a patient’s symptoms of illness. In some cases, a diagnosis leads a patient to access disease-specific medication. However, in the rare genetic disease space, the occurrence is low, as only approximately 10% of these diagnosed conditions have an available treatment.
Despite the small selection of disease-specific therapies for this patient population, patients may still have options, especially when it comes to palliating symptoms.
“We often look toward disease experts to consider what medications are more likely to be supportive,” Dr. Regier said. “This might mean considering a pain regimen, a seizure regimen, other type of symptomatic treatment, or even using some information learned to support the current patient from cases where other families may have preceded them in the odyssey.”
Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea
Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.
One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.
Unfortunately, the drawbacks do not stop there.
“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”
Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress
Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.
In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.
Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.
“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”
Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
Establishing Social Support Networks Typically Falls on the Patient and Loved Ones
Another con in rare genetic diseases is the lack of adoption across the community.
Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.
Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases
As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.
In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.
Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”
As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.
Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.
Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.
“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
Accessibility and Lack of Geneticists Often a Rate-Limiting Step
The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”
Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.
Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.
In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity
Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”
Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family — and patient — is different.
“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”
Suggested Reading
Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.
Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.