Diagnosis Made Possible with Whole Genome Sequencing

1 in 54 children are born with autism throughout the world.

A common misconception with children that have autism is that they are incapable of taking care of themselves or reaching milestones. As part of the #LightItUpBlue movement, organizations, like Baylor Genetics, are pledging to showcase the beauty in being a child with autism. In addition, BG is helping families make empowered decisions by providing genetic testing that can help detect a possible diagnosis of autism early on.

This is where we would like to introduce Whole Genome Sequencing (WGS). WGS has been a powerful tool available for researchers to understand the biology and disease pathology of the human genome.

Recently, the cost of sequencing the entire human genome has reduced drastically. Therefore, a test like WGS has become an attractive option for clinical geneticists and molecular diagnosticians.

At Baylor Genetics (BG), our history with WGS began in 2018 with the National Institutes of Health (NIH) Undiagnosed Disease Network (UDN). With this grant-funded project, BG was its only sequencing core. In 2019, BG started offering its clinical WGS services to the project’s clinical clients and their patients.

Through our experience in reviewing and interpreting WGS data, we have noticed many advantages of WGS when compared to other diagnostic tests, like Chromosomal Microarray Analysis (CMA), available in the field. A few aspects of WGS that make it a comprehensive diagnostic product include:

    • 1. The capability of calling copy number variations and structural variants at a high resolution.
    • With WGS, we are able to distinguish the differences between genes at a higher resolution. Numerous variant callers have been developed with regards to copy number variants (CNV) and structural variants (SV) calling from WGS. Efforts from clinical laboratories have gradually reached a consensus that CNV calling by the read depth algorithms can provide the optimal balance between clinical precision and recall.
    • The capability of SV calling also provides WGS with an extra feature of enhancing CNV detection when compared to CMA.
    • WGS has the advantage of covering nearly the entire human genome, enabling the possibility of a better results when new disease-related genes are defined, as compared to a limited coverage from other tests.
    • 2. The detection of intronic variants that affect splicing.
    • Intronic variants are generally not interrogated in exome sequencing and, historically, interpretation of these variants has always been a challenge. With WGS, BG is able to detect diagnostic findings in introns.
    • Recently developed tools have greatly enhanced our ability to pinpoint these intronic pathogenic variants. In addition, RNA sequencing data and its associated interpretations have become more readily available for clinical diagnoses.
    • 3. The possibility to call variants from the mitochondria genome and repeat expansion-associated diseases.
    • Mitochondrial pathogenic variants and repeat expansion mutations contribute to many genetic disorders. Some of these disorders include, metabolic, developmental, and autism. An important thing to note is that these mutation types are not interrogated by the two most common used diagnostics test, CMA and exome sequencing.
    • For WGS, however, recent technology and bioinformatics advancements have made it possible to call mitochondria variants and repeat expansions. Due to this, WGS may be considered as a comprehensive test that covers the capabilities CMA, exome sequencing, mitochondria sequencing, and repeat expansion test panels.
    • Furthermore, WGS has the capability to detect mitochondrial diseases or repeat expansion disorders in patients who present atypical clinical phenotypes, and whose actual diagnosis may be missed when they are referred to exome sequencing and CMA only.

Based off of studies BG has conducted, most of the patients who receive WGS have complex medical issues with a long diagnostic odyssey. Prior to WGS, most of these patients have unremarkable diagnostic results. In addition, WGS can be helpful for patients who have an open, differential diagnosis and have not received any type of genetic testing.

With careful consideration, WGS can be an effective method for providers and their patients when it comes to cost and time for a diagnosis. In order to make a knowledgeable choice when selecting genetic testing and with more scientific evidence being generated to support our hypothesis, it is critical for providers and their patients to understand the new data surrounding WGS.

Learn more about our clinical diagnostic test, Whole Genome Sequencing (WGS).


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