Why Should I Order Whole Genome Sequencing for My Patients?

Whole Genome Sequencing (WGS) is at the forefront of comprehensive genetic testing, designed to analyze the entire genome to find an underlying genetic cause (etiology) relating to a patient’s medical issues. WGS is quickly becoming a vital resource for prompt diagnoses in neonatal and pediatric intensive care units (NICU/PICU) for critically ill children, undiagnosed patients, and those with complex, extensive symptoms.

Continue reading to learn how WGS, combined with RNA sequencing, enhances diagnosis, informs clinical management, and ultimately improves patient outcomes.

The Diagnostic Odyssey – The Role of WGS in Transforming Complex Genetic Diagnoses

According to the National Organization for Rare Disorders, an estimated 350 million people worldwide are affected by a rare disease. In the United States alone, approximately 30 million individuals are impacted, with around 15 million affected individuals being children [1].

There are over 7,000 rare diseases, of which approximately 80% have a genetic origin. Research has revealed that over 1,500 genes contribute to neurodevelopmental disorders, more than 1,000 genes are linked to cardiovascular conditions, and upwards of 500 genes are implicated in skeletal disorders [3 – 6]. This highlights the significant role genetic testing plays in making a diagnosis and managing these conditions.

Figure 1 [2]

For individuals with rare diseases, the diagnostic journey unfortunately is often long and challenging. There are many uncertainties with making a diagnosis – from repeated tests, to misdiagnoses, to numerous consultations with different specialists. The financial, emotional, and other impacts of the diagnostic odyssey are extensive.

Genetic testing can help establish a diagnosis and possibly end the diagnostic odyssey. Once the changes in the DNA that are causing symptoms are identified, healthcare providers can implement a personalized treatment plan and improve the management of the condition, potentially leading to better health outcomes.  A genetic diagnosis not only aids the individual but also provides insights for family planning and enables the diagnosis of similarly affected relatives. This can also open the door for participation in clinical trials and access to much-needed support and services.

In the evolving landscape of genetic conditions and rare diseases, the introduction of WGS, pioneered by the Human Genome Project, was a game-changer in precision medicine and clinical diagnostics. By mapping the entire genome, WGS identifies the genetic causes of complex conditions such as epilepsy, autism spectrum disorder (ASD), and congenital anomalies.

Who Can Benefit from WGS?

Identifying the root cause of a genetic condition has significant implications for clinical management, enabling providers to make informed decisions regarding treatment, surveillance, and prognosis. WGS is particularly beneficial for patients without a diagnosis after other genetic testing, those with neurological conditions such as epilepsy, intellectual disability, or developmental delays, as well as for children with complex symptoms stemming from underlying genetic etiologies.

Several studies have shown that WGS has the potential to identify most forms of genetic variation [7]. In the pediatric population, WGS analyses have shown identification of clinically relevant variants (genetic changes) in about 40% of those with ASD and around 60% of those with intellectual disabilities.

For newborns and children in the NICU and PICU with complex medical issues, Rapid WGS may be the appropriate first-tier test for quick diagnosis and prompt intervention [8]. At-risk individuals, both adults and children, can gain crucial insights into their specific conditions and their implications for family members through WGS.

Understanding WGS and Its Diagnostic Capabilities

Unlike targeted testing that concentrates on specific genes or regions, WGS is the most advanced and comprehensive genetic testing solution. It analyzes the entire genome, encompassing both protein-coding and non-coding regions, enabling providers to detect nearly all variants present in a patient’s DNA.

These variants include single nucleotide variants (SNVs), small insertion/deletions, copy number variants (CNVs), and several tandem repeat disorders (TRDs) that might be missed by more limited standard testing approaches. In addition, WGS captures variants within mitochondrial genome, further increasing clinical utility.

Figure 2 [2]

Since WGS is able to capture variants that would be identified by panel testing, microarray, mitochondrial testing, and other tests simultaneously, it is the most comprehensive single test available [9]. This approach ensures a higher diagnostic yield, particularly for patients with rare diseases.

A study in the American Journal of Human Genetics also reveals that WGS leads to changes in medical care for 32% of individuals, saving an average of $12,000 to $15,000 per patient and avoiding approximately 525 days of hospitalization. These findings demonstrate how WGS can facilitate diagnosis, reduce hospitalization time, and eliminate unnecessary testing. [10, 11]

Comorbidities and dual diagnosis: Did you know that individuals with autism spectrum disorder (ASD) are at an increased risk for comorbidities? WGS can also help uncover dual diagnoses, where more than one genetic condition is detected and diagnosed in a patient. Having this information provides critical insights into complex medical scenarios, especially where the symptoms don’t completely match the expected disease.

Duo-trio testing: Another significant advantage of WGS is duo-trio testing, which allows for the identification of rare and de novo mutations, clarifies inheritance patterns, and minimizes false positives. This capability deepens our understanding of the complex genetic traits associated with various conditions.

Empowering Patient Care Through WGS

Did You Know? – Not All Genomes Are Equal

When healthcare providers use WGS, they access the most comprehensive insights, uncovering rare and novel variants that may be missed by standard, more targeted testing.

However, not all WGS testing offers the same level of insight, which can significantly impact diagnostic clarity. Selecting the right lab for WGS is essential to ensure the accurate detection of CNVs, TRDs, and, with the addition of RNA sequencing, the most precise answers for complex diagnoses.

Each of these considerations can strengthen the impact of WGS in delivering personalized, comprehensive patient care. Key features to consider include:

• Tandem Repeat Disorder Detection: Tandem repeat disorders (TRDs) are genetic conditions characterized by an abnormal number of repetitions of short DNA sequences within a gene. These disorders can lead to a variety of debilitating symptoms and challenges. WGS has become a useful tool for diagnosing select TRDs. Baylor Genetics’ WGS covers 29 TRDs.

• RNA Sequencing and its significance: Genetic variants, particularly variants of uncertain significance (VUS), can be challenging for clinical interpretation. Reclassification often depends on updates from gene and variant databases, along with scientific advancements that allow collection of additional functional evidence for variants. RNA sequencing (RNAseq) is increasingly used in the rare disease space to provide functional evidence. As part of our commitment to delivering answers, we offer complimentary RNAseq with all WGS orders.

• Rapid Testing for NICU/PICU: Between 30% and 50% of NICU/PICU admissions are due to birth defects or genetic conditions, with around 40% of neonates facing mortality [12]. Timely intervention is crucial for addressing these severe and complex genetic conditions. Baylor Genetics’ Rapid WGS returns written results in as few as 5 days.

• Flexible Sample Type Options: Flexibility in sample types, from blood to saliva to tissue samples, ensures that testing can proceed even when standard samples are difficult to obtain, making testing more accessible and adaptable to patient needs.

Guidelines and Recommendations for WGS

• American College of Medical Genetics and Genomics (ACMG): Recommends WGS as first-tier test for patients with congenital anomalies, developmental delay, and intellectual disability [13].
• National Society of Genetic Counselors & American Epilepsy Society: Recommends WGS as a first-tier test for individuals with unexplained epilepsy [14].
• American Academy of Pediatrics (AAP): Endorses WGS as an effective approach for achieving genetic diagnoses, emphasizing the utility of Rapid WGS in neonatal care for critically ill infants [9, 15].
• International Precision Child Health Partnership (IPCHiP) recommends WGS as a first-tier test for NICU patients with unexplained hypotonia [16].

These guidelines and acknowledgements on the utility of WGS highlight its role in a number of clinical settings, empowering providers to deliver precise, life-changing diagnoses.

The Baylor Genetics Advantage in WGS

At Baylor Genetics, we proudly offer WGS, our most advanced and comprehensive genetic testing solution. This innovative approach analyzes 98% of the genome, encompassing both protein-coding exons and non-coding regions, providing an unparalleled depth of insight into genetic conditions.

Our WGS goes beyond basic analysis, incorporating the examination of SNVs, CNVs, the mitochondrial genome, and regions of homozygosity (ROH) as well as 29 TRDs. We deliver standard results in three weeks, allowing for prompt clinical decision-making.

Our Rapid WGS is a vital tool that delivers comprehensive written results starting in just five days. This expedited turnaround time allows for timely clinical decisions and provides life-saving insights for patients in the NICU/PICU.

The addition of complimentary RNA sequencing enhances our WGS by providing deeper insights into variant pathogenicity, including splicing impacts.

“Variants of unknown significance (VUS) can be difficult for providers to interpret, and may lengthen the diagnostic odyssey for patients,” said Christine Eng, MD, Chief Medical Officer and Chief Quality Officer at Baylor Genetics. “By enhancing our Whole Genome and Whole Exome Sequencing tests with the addition of RNA sequencing, we increase the potential to re-classify uncertain variants and provide deeper understanding of a patient’s condition, treatment options, and health management.”

Additionally, we also offer WGS Reanalysis, enabling healthcare providers to revisit and reinterpret previous results for their patients who had WGS performed at Baylor Genetics. This service is particularly valuable for patients with evolving clinical phenotypes or new symptoms.

Recognizing the complexities involved in interpreting genetic test results, Baylor Genetics offers dedicated genetic counseling services to support our healthcare providers. Our genetic counselors are available to assist providers navigating the intricacies of genetic testing, ensuring that you and your patients receive the highest possible level of clarity at all stages of the testing process.

Our state-of-the-art laboratory is complemented by a team of medical geneticists, genetic counselors, and faculty and researchers from Baylor College of Medicine. Through these collaborative efforts, we are advancing discoveries in research and testing.

Is WGS My Patient’s Best Option?

WGS is rapidly establishing itself as a first-tier test for pediatric conditions, by delivering comprehensive answers with a superior diagnostic yield over other testing methods [13, 14]. Its ability to analyze a broad spectrum of variants proves essential for diagnosing complex conditions. Genomic sequencing results that do not lead to a definitive diagnosis can still be medically actionable, informative, and contribute to shared decision-making [17, 18].

Ultimately, the decision to utilize WGS should be made by the healthcare provider based on the individual patient’s needs, clinical context, and family history. By carefully evaluating these factors, providers can determine if WGS is the right choice for their patients, paving the way for enhanced diagnostic clarity, and improved management of genetic conditions.

At Baylor Genetics, we are committed to empowering you throughout this journey, delivering meaningful answers to help end the diagnostic odyssey for your patients through advanced genetic testing.

We invite you to explore our comprehensive suite of WGS offerings to see how we can assist you in improving patient care.

References

1. Understanding rare diseases (raredisease.org).
2. 2024 NSGC EBS This or That.pptx (sharepoint.com).
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4. Williams K, Carson J, Lo C. Genetics of Congenital Heart Disease. Biomolecules. 2019;9(12):879.
5. Spielmann, N., Miller, G., Oprea, T.I. et al. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy. Nat Cardiovasc Res 1 2022, 157–173.
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12. Weiner J, Sharma J, et. al. How infants die in the neonatal intensive care unit: trends from 1999 through 2008. Arch Pediatr Adolesc Med. 2011;165(7):630-634.
13. Manickam K, McClain MR, et al. 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.
14. Smith L, Malinowski J, Ceulemans S, et al. J Genet Couns. 2022 Oct 24; 32:266–280.
15. Wayne Grody, Barry Thomson, et al, Pediatrics (2013) 132 (Supplement_3): S211–S215.
16. Morton SU, Christodoulou J, Costain G, et al. JAMA Neurol. 2022 Apr1;79(4):405-412.
17. Krantz et al. Effect of whole genome sequencing on the clinical management of acutely ill infants with suspected genetic disease: the NICUSeq Randomized Time-Delayed Trial. JAMA Pediatrics. 2021.
18. Genetics Corner: Clinical Implementation and Improved Access of Whole-Genome Sequencing in the NICU: Learnings from a Virtual Educational Event.