Why Everyday Counts in the Intensive Care Unit: How Rapid Whole Genome Sequencing is the Most Comprehensive Testing Solution
Intensive care units (ICUs) are dedicated to providing critical care to patients with life-threatening conditions. Many genetic disorders present in infancy and childhood, and neuromuscular disease in particular can be challenging to diagnose and treat. Genetic neuromuscular disorders affect the nervous system and muscles, leading to a wide range of symptoms that can be difficult for clinicians to identify and manage. Whole genome sequencing (WGS) has emerged as a valuable tool in genetics and can quickly improve the way we identify, understand, and manage neuromuscular disorders in younger patients. Here, along with genetic disorders and neuromuscular disorders, we will explore how rapid whole genome sequencing (rWGS) is reshaping the diagnosis of neuromuscular disorders in ICUs, ultimately improving the lives of young patients and their families.
UNDERSTANDING NEUROMUSCULAR DISORDERS
Neuromuscular disorders encompass a heterogeneous group of conditions that affect the nervous system and muscles1. These disorders can manifest in a variety of ways, including muscle weakness, muscle wasting, difficulty with motor skills, and even respiratory failure. Some common neuromuscular disorders in children include Duchenne muscular dystrophy and spinal muscular atrophy, among others.
Diagnosing neuromuscular disorders can be incredibly challenging due to the broad range of symptoms and the overlapping clinical features with other diseases2. In many cases, a precise diagnosis may involve years of testing and evaluation, known as a diagnostic odyssey. These delays can result in significant emotional and financial burdens on families and may limit the effectiveness of treatments. The lack of an accurate diagnosis can lead to longer hospital stays, and poor outcomes in up to 40% of patients.
THE ROLE OF RAPID WHOLE GENOME SEQUENCING AND RAPID WHOLE GENOME SEQUENCING
The “rapid” aspect of whole genome sequencing (WGS) is especially important in acute clinical settings, where timely results are critical for patient care. Advances in sequencing technologies have made it possible to obtain genomic data quickly, making rapid WGS (rWGS) an invaluable tool for clinicians. By providing the most comprehensive and detailed view of a patient’s genetic makeup, rWGS is a diagnostic tool for identifying genetic disorders, including neuromuscular disorders. Below are additional advantages to using WGS:
- Early Diagnosis: One advantage of WGS is its ability to detect genetic variants associated with neuromuscular disorders at an early stage of life. This early diagnosis can help healthcare providers promptly initiate treatment and intervention strategies.
- Identifying Rare Mutations: Neuromuscular disorders can result from rare or novel genetic mutations that may not be identifiable through other genetic testing methods, whereas WGS can identify intronic variants and trinucleotide repeats. WGS can identify these rare mutations by looking at the whole genome, which allows for a more accurate diagnosis and a better understanding of the disorder’s underlying genetic basis.
- Tailored Treatment Plans: Once a neuromuscular disorder is accurately diagnosed through WGS, healthcare providers can develop personalized treatment plans that are tailored to the specific genetic profile of the patient. This precision medicine approach can optimize the effectiveness of therapies and reduce potential side effects.
GENETIC DISORDERS
Spinocerebellar ataxia 2 (SCA2): SCA2 is a progressive, neurodegenerative disorder with neuromuscular features characterized by a range of symptoms that primarily affect motor coordination3. It is a type of spinocerebellar ataxia, which is a group of hereditary ataxias caused by genetic mutations leading to the degeneration of the cerebellum and its associated pathways.
SCA2 is caused by a mutation in the ATXN2 gene, which leads to the abnormal expansion of a CAG trinucleotide repeat. This mutation results in an altered form of the ataxin-2 protein, which accumulates in neurons, particularly in the cerebellum, brainstem, and spinal cord, disrupting their normal function.
The onset of symptoms in SCA2 typically occurs in adulthood, with patients initially experiencing difficulties in coordination, such as unsteady gait and poor hand-eye coordination. As the disease progresses, other symptoms may develop, including slow eye movements, speech difficulties, and tremors. Some individuals may also experience non-motor symptoms like cognitive impairment, sleep disturbances, and depression.
Currently, there is no cure for SCA2, and treatment primarily focuses on managing symptoms and improving quality of life. This may involve physical therapy to aid in mobility and coordination, speech therapy, and medications to control specific symptoms such as muscle stiffness or tremors. Early diagnosis and intervention can be beneficial in managing the progression of symptoms and providing support for patients and their families.
Progressive myoclonic epilepsy type 1 (EPM1): Also, known as Unverricht-Lundborg disease. This is a rare genetic disorder characterized by a combination of myoclonus, epileptic seizures, and other symptoms4. Symptoms typically begin in early childhood or adolescence.
The most prominent feature of EPM1 is myoclonus, which are sudden, brief, involuntary muscle jerks. These jerks are often triggered by various stimuli, including stress, fatigue, or even light. In addition to myoclonus, patients with EPM1 experience generalized tonic-clonic seizures, which are convulsions that affect the entire body. Over time, the seizures may become more frequent and severe.
Neurological deterioration is another key aspect of EPM1. This can manifest as difficulties with coordination and balance (ataxia), cognitive decline, and speech disturbances. As the disease progresses, these symptoms can significantly impact daily activities and quality of life.
PME1 is caused by mutations in the CSTB gene, which leads to a deficiency of an enzyme called cystatin B. This enzyme is thought to play a role in protecting neurons from damage. The inheritance pattern of PME1 is autosomal recessive, meaning a patient must inherit two copies of the mutated gene, one from each parent, to develop the condition.
Due to its progressive nature, individuals with PME1 often require increasing levels of care as the disease advances.
Many next generation sequencing-based epilepsy panels do not include trinucleotide repeat assessment. rWGS offers concurrent testing of many trinucleotides repeat conditions in genes such as CSTB while also detecting sequence variants.
Duchenne Muscular Dystrophy (DMD): This rare and devastating genetic disorder primarily affects males, characterized by progressive muscle weakness and wasting5. It is caused by deleterious mutations in the DMD gene, which encodes the dystrophin protein—a critical component of muscle fibers.
DMD is an X-linked recessive disorder, meaning it predominantly affects males. Females can be carriers of a harmful mutation in the DMD gene can have muscle weakness and are at risk for cardiomyopathy, while other females may not exhibit symptoms at all. However, males with a single copy of the mutated gene develop the disease. Dystrophin is a large protein involved in maintaining the structural integrity of muscle cells. Deleterious mutations in DMD lead to the absence or deficiency of functional dystrophin, resulting in muscle fiber fragility and progressive degeneration.
Clinically, DMD will typically present in early childhood, with symptoms such as muscle weakness and delayed motor milestones. Affected individuals often have difficulty walking and may require a wheelchair by their teens. Muscle wasting continues, eventually affecting respiratory and cardiac muscles, significantly reducing life expectancy. Early diagnosis and intervention are crucial to improve the quality of life for individuals with DMD.
A primary advantage of WGS is its ability to detect a range of mutations in the DMD gene, including point mutations, small insertions, or deletions (indels), and larger structural variations in a singular test. Traditional diagnostic approaches, like Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA), are limited in their ability to detect all mutation types. Certain treatments for the condition can only be utilized when a patient has a particular genetic cause.
Myasthenia Gravis (MG): an autoimmune neuromuscular disorder that affects the neuromuscular junction, causing muscle weakness and fatigue6. MG can occur at any age, including in children. It is characterized by the production of autoantibodies that target the acetylcholine receptors (AChR) or other proteins involved in neuromuscular transmission. While the exact cause of MG remains unclear, there is evidence to suggest a genetic component in the disease’s development.
Several genes have been implicated in the susceptibility to Myasthenia Gravis:
- HLA: Human leukocyte antigen (HLA) genes, particularly the HLA-DR3 and HLA-DR4 alleles, have been associated with an increased risk of MG. These genes play a crucial role in the immune system by presenting antigens to immune cells. Certain HLA alleles may make individuals more prone to developing autoimmune diseases, including MG.
- PTPN22: The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene is involved in regulating immune responses. Certain variants of this gene have been linked to an increased risk of autoimmune diseases, including MG. These variants may lead to abnormal immune cell activation and contribute to the development of MG.
- CTLA4: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is another gene involved in immune regulation. Variations in the CTLA4 gene have been associated with MG susceptibility. Altered CTLA-4 function can affect the balance of immune responses and potentially contribute to autoimmune reactions.
- TNIP1: TNFAIP3 interacting protein 1 (TNIP1) is involved in the regulation of inflammation and immune responses. Genetic variations in TNIP1 have been linked to MG, suggesting that abnormalities in immune regulation may play a role in the disease.
It is important to note that while these genetic factors may increase the risk of developing MG, they do not guarantee its onset. MG is a complex disease influenced by both genetic and environmental factors. Environmental triggers, such as infections or stress, can also play a significant role in the development and exacerbation of MG.
Understanding the genetic basis of MG is essential for advancing our knowledge of the disease and developing targeted therapies. Whole genome sequencing is a valuable tool that gives the full picture of not only MG, but several disorders mentioned above with SMA (Spinal Muscular Atrophy) and DMD.
BAYLOR GENETICS AND RAPID WHOLE GENOME SEQUENCING
rWGS from Baylor Genetics offers several advantages in the Neonatal Intensive Care Unit (NICU) and Pediatric Intensive Care Unit (PICU) settings. These advantages include:
- Fast Diagnosis: rWGS can provide a quick and accurate diagnosis for critically ill newborns and children with complex medical conditions. Baylor Genetics provides a written report of rWGS test results in as few as five days.
- ~38% diagnostic yield versus 21% for standard genetic testing including chromosomal micro array, single gene testing, and panels.
- End the Diagnostic Odyssey: Many children with rare or undiagnosed genetic conditions go through a lengthy diagnostic odyssey, visiting multiple specialists and undergoing numerous tests. Baylor Genetics and rWGS can significantly shorten this process, reducing the physical and emotional burden on patients and their families.
- Avoidance of Invasive Procedures: In some cases, a genetic diagnosis obtained through rWGS and quick turn-around-time can help avoid unnecessary invasive procedures and surgeries, as it may reveal non-genetic causes for a patient’s symptoms.
- Early Intervention: Identifying genetic disorders early in a child’s life allows for early intervention and management. This can include appropriate medications, therapies, and lifestyle modifications that can improve the patient’s quality of life.
- Enhanced Collaboration: These technologies promote collaboration among healthcare providers, geneticists, and researchers, leading to a more comprehensive approach to patient care.
CONCLUSION
Rapid whole genome sequencing has transformed the diagnosis and management of neuromuscular disorders in both neonatal and pediatric intensive care units. By providing early and accurate diagnoses, identifying rare mutations, and enabling personalized treatment plans, WGS offers hope to young patients and their families.
As science and clinical utility with WGS technology continues to advance, it is likely to play an even more prominent role in the early detection and treatment of neuromuscular disorders in young patients. With ongoing research and collaboration among healthcare professionals, geneticists, and bioinformaticians, we can look forward to a future where more children with neuromuscular disorders receive timely and effective interventions, ultimately leading to better outcomes and improved overall health and well-being.
If you would like get in touch with Baylor Genetics or want to learn more about ordering a rapid genome sequencing test, please click here: https://www.baylorgenetics.com/contact/
References:
- https://www.sciencedirect.com/topics/neuroscience/neuromuscular-disorder
- https://www.nyp.org/neuro/neuromuscular-disorders/treatment
- https://www.ncbi.nlm.nih.gov/books/NBK1275/
- https://www.ncbi.nlm.nih.gov/books/NBK1142/
- https://www.duchenne.com/about-duchenne
- https://www.pennmedicine.org/for-patients-and-visitors/patient-information/conditions-treated-a-to-z/myasthenia-gravis
