Whole Genome Sequencing: The Russian Nesting Doll of Genetic Testing?

Quantum leaps of technological advancement in sequencing methodology over a decade ago spearheaded the current genomic medicine revolution. This new methodology – massively parallel sequencing, also known as next-generation sequencing (NGS), made it feasible to sequence large areas of genomes at a reasonable cost and within a clinically relevant time frame.

Application of NGS-based clinical tests have transformed genetic testing by increasing diagnostic yield and decreasing the time to reach a diagnosis. This has significantly improved our capability in diagnosing difficult-to-diagnose genetic disorders and has provided the ability to molecularly target cancer mutations.

Currently, NGS testing in clinical laboratories comes in three main categories: disease-focused, exome sequencing, and genome sequencing. The first testing introduced was disease-focused, targeted gene panels. This method was a cost-effective alternative to replace labor intensive standard methods of sequencing pieces of genes at a time by Sanger sequencing. Further understanding and enhancements of NGS chemistry facilitated developing assays in a fast and cost-effective way to sequence all the protein coding regions of the genome rather than a few select genes of interest.

Exome sequencing was a game changer in clinical genomic diagnostics and able to provide a reliable and sensitive detection of all coding variants (SNVs, Indels). Exome sequencing is now established as an efficient method to identify possible disease-causing mutations. Baylor Genetics has pioneered the use of its Whole Exome Sequencing (WES) in diagnosing rare diseases both in pediatric and prenatal settings. WES has several technological limitations with the most important being the inability to examine genomic regions beyond protein coding.

Thus, to fully realize the potential of clinical genomic analyses, understanding the impact of full spectrum variations across the whole genome is required, not just the protein coding areas of genome. The non-coding genome is substantially larger than the protein-coding region alone, and contains structural, regulatory, and transcribed information. It is now known that many non-coding regions can affect gene activity and protein production.^{1, 2} Baylor Genetics’ Whole Genome Sequencing (WGS) is able to carefully study the important non-coding regions, non-coding RNAs, and mRNA splicing in addition to all protein-coding genes. Due to the decrease in cost of NGS, it is now conceivable to sequence the entire genome through comprehensive sequencing the entire base-by-base analyses in high resolution.

While there are many benefits to WGS, there can be a few barriers for wide-spread adoption of WGS in a clinical setting. Some of these barriers include:

1. WGS is not yet reimbursed by some private payors.
2. Knowledge of the role for non-coding regions is still not fully developed. More ongoing research will help overcome this barrier.
3. Interpretation of large data sets require experience and resources, which many clinics are lacking.

The Role of Genome Sequencing in Genomic Diagnostics

In addition to diagnosis of rare Mendelian diseases and being able to identify targetable genomic alterations in cancer, WGS has applications in other areas such as pharmacogenomics, population genetics, risk assessment of medically actionable mutations in the Centers for Disease Control and Prevention’s Tier 1 genomic disorders (Hereditary Breast and Ovarian Cancer Syndrome, Lynch Syndrome, and Familial Hypercholesterolemia) and HLA typing.

Why Whole Genome Sequencing at Baylor Genetics?

Baylor Genetics has been a pioneer in creating state-of-the-art and first-in-class genomic solutions for over four decades. A few examples of groundbreaking clinical test launches are chromosomal microarray, WES and now, WGS. Baylor Genetics serves as the only sequencing core of the no. 1 NIH-funded Undiagnosed Diseases Network (UDN) providing WES and WGS capabilities. Additionally, Baylor Genetics is playing a crucial role in defining and communicating best practices for the clinical application of WGS in the diagnosis of genetic diseases through a multi-institutional consortium of prestigious institutions – Medical Genome Initiative.

With being the sole clinical sequencing core for the UDN, Baylor Genetics has lot of experience in interpretation of WGS. American Board of Genetic Counseling certified genetic counselors and American Board of Medical Genetics and Genomics certified laboratory directors are available for consultation of the results. In addition, our reports are streamlined and are easy to interpret.

• Indications for Testing:
  • Multiple congenital anomalies
  • Autism spectrum disorders
  • Neurodevelopmental disorders
  • Developmental delay
  • Intellectual disability
  • Failure to thrive
  • Dysmorphic features
  • Epilepsy syndromes
  • Patients with an extensive differential diagnosis
• Sample Types:
  • Peripheral blood
  • Cultured cell lines
  • Extracted DNA

To learn more about WGS at Baylor genetics please visit,  www.baylorgenetics.com/whole-genome-sequencing/.

Conclusions

Over the last decade, advances in NGS have transformed genetic testing by providing a comprehensive look into the entire genome, thus circumventing all limitations of the enrichment based NGS testing. This includes exome sequencing and targeted NGS multigene panels.

Genome Sequencing has the potential to transform genetic diagnostics of patients with rare Mendelian disorders, newborn patients with life threatening disorders, and help identify targetable mutations in cancer. Despite its superior capabilities and increased diagnostic yield, compared to currently available NGS tests, widespread adoption of WGS is hampered by lack of uniform reimbursement.

References:

1. Williams, S.M., An, J.Y., Edson, J. et al. An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder. Mol Psychiatry 24, 1707–1719 (2019).
2. Zhang, J., Lee, D., Dhiman, V. et al. An integrative ENCODE resource for cancer genomics. Nat Commun 11, 3696 (2020).
3. https://www.cdc.gov/genomics/implementation/toolkit/tier1.htm
4. IASLC Thoracic Oncology (Second Edition), 2018 Pages 95-103e2, Elsevier publications.