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Is whole genome sequencing the new first-line test for children with genetic diseases?

Posted by Katherine Lawless on Tue, Feb 19, 2019 @ 13:02 PM

WGS blog imageCongenital anomalies and genetic disorders are the leading cause of death in children less than ten years old and affect about six percent of live births. For children with suspected genetic disorders, it is crucial to establish an early etiologic diagnosis for a prompt implementation of precision medicine and to enable optimal outcomes to guide clinical decisions. The challenge, however, is the lack of etiologic diagnosis.

Whole genome sequencing (WGS) is a relatively new method for genetic diagnosis and many publications are discussing its clinical significance. The National Human Genome Research Institute (NHGRI) highlighted two publications as notable 2018 accomplishments concerning sequencing and the clinical implementation for children with genetic disorders.  

As published in this clinical trial, Rapid Whole Genome Sequencing (rWGS) has proven to provide much faster diagnoses than traditional clinical testing, including Whole Exome Sequencing (WES) and standard Whole Genome Sequencing. Farnaes L et al claim that rWGS is defined as diagnosing a genetic disorder in time to change an acute medical or surgical management. They also claim rWGS decreases infant morbidity, mortality and hospital cost; Clark MM et al performed a meta-analysis of the diagnostic and clinical utility of WGS and WES, as compared to the traditional chromosomal microarray (CMA). In this blog, we will explore their findings and learn why they claim whole-genome sequencing should be the first-line genomic test for children with genetic diseases. [1][2]

1. WGS versus CMA for the 1st-line genomic test for children with genetic diseases

CMA is traditionally recommended as the first-line genomic test for children with several types of genetic diseases which include intellectual disability, developmental delay, autism spectrum disorder, and multiple congenital anomalies. Clark MM et al performed a meta-analysis of studies published from 2011 to 2017 to determine the rate of clinical utility of WGS compared to WES and CMA.

Diagnosis for genetic disorders by WGS was 8.3 times greater than CMA, as reported by Clark MM et al, suggesting CMA should no longer be considered as the first-line genomic test for children with suspected multiple genetic diseases but rather WGS for first-line etiologic diagnosis. 2

2. rWGS decreases infant morbidity

Farnaes et al examined many different cases involving infants with suspected genetic disorders and how rWGS prevented or could have prevented morbidity. rWGS predicted precision medicine was evaluated to have prevented morbidity in 61% of infants compared to 0% with standard care.1 Here are two examples:

Case #1: An infant identified as having a genetic disorder was discharged after 8 days of extensive evaluation with no diagnosis (their rWGS Spanish consent forms were not approved). The infant was then re-admitted 4 days thereafter due to complications. Finally, rWGS was performed and the infant was diagnosed with Niemann-pick disease, type C1. Had rWGS been performed on his first admission, the second admission would not have been necessary.

Case #2: A Neonate was admitted at birth to the NICU due to respiratory distress. rWGS was performed right away and he was diagnosed with Nemaline Myopathy, avoiding the need for a muscle biopsy.

rWGS had a significantly higher diagnosis sensitivity than standard care, gave a provisional diagnosis in about 26-48 hours, and avoided morbidity in 26% of infants, major morbidity in 10% of infants, and reduced the likelihood of acute mortality in 2% of infants. Therefore, reducing morbidity in infants.1

3. rWGS decreases the cost of care

Not only does rWGS reduce morbidity in infants but it can also reduce the cost downstream. It might be hard to believe since rWGS is considered to be expensive; however, Farnaes et al proved that rWGS in fact would save cost.

Out of the many studies they performed, one involved a study of 6 infants where rWGS was used to reduce the length of stay by 124 days, and costs of inpatient professional and facility by at least $803,200 USD1.


Both teams presented evidence that Whole-Genome Sequencing (and rWGS) should be the first-line genomic test for children with suspected genetic diseases, for it has a higher rate of clinical and diagnostic utility, decreases morbidity and overall clinical costs than standard genomic testing.

In order for WGS to enable timely high-quality results, it must also rely on important factors such as reliable and high quality sample input. Saliva or oral swab collection for DNA has obvious benefits over blood, such as improving donor compliance due to non-invasive collection, but has also been proven to be equivalent to blood for downstream analysis, including WGS as reported in many posters and publications. Here are two recent examples:

“WGS was subcontracted to the Kinghorn Centre for Clinical Genomics (Australia) and conducted on an Illumina HiSeq X platform…Saliva samples were collected using Oragene OG-500.” PGP-UK: a research and citizen science hybrid project in support of personalized medicine, published by Rajanayagam S et al.[3]

“Oral swab collection [ORAcollect] should be considered a viable non-invasive alternative to blood collection for use in genomic testing.” The Impact of Bacterial DNA Contamination in Oral Swabs on Whole Genome Sequencing, presented by GenomeONE at ACMG 2017.[4]

DNA Genotek offers a variety of saliva and oral-based collection devices for use with infants and children of various ages and abilities; furthermore, Oragene•Dx and ORAcollect•Dx are FDA cleared saliva DNA collection devices to be used for in vitro diagnostics+.  If you are interested in evaluating saliva or oral samples as a sample type for your own analysis, including WGS, please contact info@dnagenotek.com.

Related topics: 

High quality libraries for human WGS with direct saliva Input, presented by Illumina and DNA Genotek Inc.

Blood vs. saliva: analysis of the effect of sample type on variant calling confidence for human Whole Genome Sequencing[5] published by DNA Genotek Inc. and Seven Bridges Genomics Inc. in 2014.

† Oragene•Dx and ORAcollect·Dx have been FDA cleared for in vitro diagnostic use in the USA with the eSensor® Warfarin Sensitivity Saliva Test.


[1] Farnaes L et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. Genomic Medicine. 3:10 (2018).

[2] Clark MM et al. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. Genomic Medicine. 3:16 (2018).

[3] Rajanayagam S et al. PGP-UK: a Research and Citizen Hybrid Project in Support of Personlized Medicine. bioRxiv. (2018).

[4] Dinger M et al. The Impact of Bacterial DNA Contamination in Oral Swabs on Whole Genome Sequencing. GenomeOne. (2017).

[5] Rakocevic et al. Systematic multi-sample analysis of the effect of sample type (blood vs saliva) on variant calling confidence for WGS. MK-00360 Issue 1/2014-04.

Tags: DNA saliva cost, Oragene RNA, whole genome sequencing

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This blog is intended to provide information to educate readers about molecular testing and genetic sample collection and DNA Genotek products.  Some of the information on this blog represents emerging scientific research or data developed for research purposes only. More information here.

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