Navigating the Maze: Clinicians Cannot Treat What Is Not Diagnosed
In the realm of medicine, diagnosis can be half the battle. Clinicians, despite their extensive training and expertise, can find themselves perplexed when confronted with rare genetic diseases. These conditions can be incredibly challenging to diagnose and treat, especially when they affect infants and children in intensive care units. However, there have been significant scientific advances in the form of genetic testing, specifically, whole genome sequencing (WGS) and whole exome sequencing (WES), which offer new hope in unraveling the mysteries of rare diseases.
Rare diseases, sometimes called orphan diseases, are defined by their individual low prevalence. Collectively, there are thousands of rare diseases, many of which exhibit variable, obscure, or overlapping symptoms. While there is no globally accepted threshold for rare diseases, the United States Food and Drug Administration (FDA) characterizes them as affecting fewer in 200,000 people; this translates to one in 1,700 people in the U.S. being affected by a rare disease. The National Organization for Rare Diseases (NORD) estimates that there are about 350 million people affected by rare diseases globally.
Rare diseases typically affect multiple organ systems and can present with a range of symptoms, such as seizures, respiratory failure, cardiac failure, and muscle weakness, among others. Symptoms appear early in childhood, with most individuals with rare diseases being under 5-years-old . Most rare diseases – about 80% – have a genetic basis . As with common diseases, clinicians rely on a combination of clinical symptoms, medical history, laboratory tests, and medical literature to diagnose rare diseases. However, because of how rare they can be, there is limited knowledge and awareness of these conditions.
THE DIAGNOSTIC ODYSSEY
Traditionally, the diagnosis and treatment of most common illnesses follows a straightforward path. For individuals with rare diseases, this journey to diagnosis can be complex and arduous. The ‘diagnostic odyssey’ refers to the time it takes to receive a correct diagnosis. Many survey-based studies on adults and children with rare diseases show that receiving a diagnosis can involve several visits with multiple specialists, unclear results, and incorrect diagnoses, leading to significant delays in establishing a diagnosis and receiving treatment . According to data from the Global Commission of Rare Diseases International and the NIH Office of Rare Diseases Research (ORDR), it can take more than 5 years to arrive at the right diagnosis, and many individuals remain undiagnosed throughout their lifetime [4, 5]. This process often leaves patients and families grappling with uncertainty and frustration while facing physiological, emotional, and financial challenges.
- One significant reason for why it can take so long to reach the right diagnosis is the difficulty in accessing specialized care. There is a shortage of specialists, including medical geneticists  that have expertise in rare diseases. This compounds the issue of access to appropriate genetic testing. While in-house tests at clinics and/or hospitals are valuable tools for diagnosing many common conditions, there is a chance they may not be appropriate or comprehensive enough to identify rare diseases. Additionally, complex genetic data can be challenging to interpret, leading to inconclusive or misinterpreted results. Advanced genetic testing methods like WGS and WES are especially useful tools in the quest for a diagnosis, offering comprehensive coverage, increased sensitivity, and personalized treatment options (more on this later). As genetic testing and science continue to advance, the hope is that the diagnostic odyssey will become shorter and less uncertain for those affected by rare diseases.
WHERE TRADITIONAL DIAGNOSTIC METHODS MAY FALL SHORT
A recent article from The Harvard Gazette tells the story of Rithvik, a young boy who struggled with mysterious health issues since birth. Rithvik, diagnosed with “prune belly syndrome” at birth, suffered from various multisystemic health problems primarily involving smooth muscles. He had over 20 surgeries and medical interventions, but the root cause of his condition remained unknown, leaving his family and doctors in a state of frustration and uncertainty.
Around the same time, Dr. Patricia Musolino, a neurocritical care fellow at Massachusetts General Hospital, encountered a similar case involving a 2-year-old patient. Delving deeper into the genetics of her patient, her team discovered a mutation in the ACTA2 gene, which is responsible for smooth muscle function. This breakthrough helped identify a condition known as Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS), shedding light on a previously unknown genetic disorder.
Rithvik’s doctors at Boston Children’s Hospital suspected MSMDS, but his genetic tests did not identify any mutations in the ACTA2 gene. His doctors then sought help from the Undiagnosed Diseases Network, a collaborative initiative of top research institutions, and a more detailed investigation eventually identified a mutation in a microRNA gene MIR145. This gene was known to be responsible for regulating smooth muscle genes, but it took many months of expert evaluation and laboratory experiments to confirm that MIR145 affects ACTA2, causing similar MSMDS symptoms as an ACTA2 mutation would. This discovery was pivotal, as it demonstrated that mutations in non-protein-coding parts of the genome could lead to complex syndromes like MSMDS. The identification of this mutation provided Rithvik’s family with answers and allowed for more targeted treatment, though it did not offer a cure. Research on MSMDS has since progressed, with successful gene therapy in mice models, offering hope for future treatments.
This story underscores the complexities of genomic medicine and the importance of collaborative research in unraveling the mysteries of rare genetic disorders. It highlights the potential of genetic testing and personalized medicine in diagnosing and treating conditions that were once unsolvable, paving the way for new discoveries and treatments in medical genetics.
ADVANCES IN GENETIC TESTING
Advances in genetic testing, specifically WES and WGS, allow clinicians and researchers to cast a wide net while examining a patient’s DNA. WGS involves sequencing an individual’s entire genome, which contains all their genetic information. It is a comprehensive approach that can uncover a wide range of genetic variations, from single nucleotide changes to larger structural alterations in the DNA. WES focuses on sequencing the exome, which comprises the coding regions of genes responsible for producing proteins. While it covers about 1-2% of the entire genome, it includes the majority of disease-causing mutations. WES is particularly well-suited for diagnosing rare diseases with known genetic bases. Many professional guidelines, including the American Society of Medical Genetics and Genomics (ACMG) strongly recommend WES or WGS as a first- or second-tier test for individuals with congenital anomalies, developmental delays, and/or intellectual disabilities .
A recent example from Baylor Genetics that highlights the impact of up-to-date, comprehensive genetic testing is the story of a 3-day old patient in the NICU. The patient presented with low muscle tone, feeding issues, elongated fingers, retrognathia, and abnormality of the gingiva. While considering various conditions like spinal muscular atrophy, metabolic disorders, Prader-Willi Syndrome, and Angelman Syndrome in the differential diagnosis, the patient’s provider ordered rapid trio whole genome sequencing. This test was completed in five days, and it identified a paternally inherited deletion on chromosome 15, establishing a diagnosis of Prader-Willi syndrome (PWS).
This quick and precise diagnosis helped the NICU team implement appropriate management consistent with standard of care for PWS. In addition, knowing the specific genetic cause and inheritance pattern could aid reproductive planning and managing future pregnancy risks. Traditional testing for PWS/AS usually can take weeks with multiple tests, but Baylor Genetics’ rapid WGS gave results in five days, analyzing various genetic conditions in a single test.
In many instances, especially when symptoms are obscure or non-specific, genetic testing can be critical in the diagnostic process. Genetic testing can help detect causative mutations in known genes and identify mutations in previously unknown disease-genes. In some cases, these discoveries can facilitate personalized treatment; once a rare disease is diagnosed through genetic testing, doctors may be able to tailor treatment plans to the specific genetic profile of the patient. This approach, known as precision medicine, holds great promise for improving outcomes and reducing side effects, as it considers the patient’s genetic profile.
RARE DISEASE DAY
Rare Disease Day, observed annually on the last day of February, is a global event dedicated to raising awareness for rare diseases and their impact on patients’ lives. It is an international advocacy day that brings together individuals, healthcare professionals, researchers, and policymakers to shed light on rare diseases, which often lack sufficient research, treatment options, and support. In 2024, the theme for Rare Disease Day is “Bridging the Gap Between Diagnosis and Treatment.” This theme emphasizes the critical need for better access to treatments and care for individuals with rare diseases, recognizing the unique challenges they face.
The day is marked by events and activities globally, including conferences, patient-led initiatives, social media campaigns, and community events. These activities aim to educate the public, increase support for affected individuals, and advocate for policy changes. Personal stories from patients and their families play a crucial role in these events, putting a human face on the struggles associated with rare diseases.
The journey of diagnosing and treating rare diseases, often described as a “diagnostic odyssey,” is fraught with challenges but illuminated by the promise of genetic testing. Traditional methods may fall short in unraveling these complex conditions, leaving patients and families in limbo. However, breakthroughs in genomic medicine, as illustrated by the cases above, demonstrate the transformative potential of WGS and WES. These advanced techniques not only aid in pinpointing elusive diagnoses, but also pave the way for personalized treatments, marking a significant leap forward in medical science. The importance of such advancements is further highlighted during events like Rare Disease Day, emphasizing the need for continued research, improved healthcare policies, and international collaboration. As we bridge the gap between diagnosis and treatment, the hope for those affected by rare diseases grows stronger, fostering a future where medical mysteries become solvable puzzles, leading to better outcomes and enhanced quality of life.
If you would like to get in touch with Baylor Genetics or want to learn more about our comprehensive portfolio of genetic tests, please click here: https://www.baylorgenetics.com/contact/
Scientific contributions by Arpita Neogi, CGC.
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- Rare diseases, common challenges. Nat Genet 54, 215 (2022). https://doi.org/10.1038/s41588-022-01037-8
- Bauskis, A., Strange, C., Molster, C. et al. The diagnostic odyssey: insights from parents of children living with an undiagnosed condition. Orphanet J Rare Dis 17, 233 (2022). https://doi.org/10.1186/s13023-022-02358-x
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- Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM; ACMG Board of Directors. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021 Nov;23(11):2029-2037. doi: 10.1038/s41436-021-01242-6. Epub 2021 Jul 1. PMID: 34211152.