Whole-Genome Sequencing Can Identify Clinically Relevant Variants from a Single Sub-Punch of a Dried Blood Spot Specimen

Author:

McBride David J.1ORCID,Fielding Claire1,Newington Taksina1,Vatsiou Alexandra1,Fischl Harry1,Bajracharya Maya1,Thomson Vicki S.1,Fraser Louise J.1,Fujita Pauline A.2,Becq Jennifer1,Kingsbury Zoya1,Ross Mark T.1,Moat Stuart J.34ORCID,Morgan Sian5

Affiliation:

1. Illumina Cambridge Ltd., Cambridge CB21 6DF, UK

2. Illumina Inc., San Diego, CA 92122, USA

3. Wales Newborn Screening Laboratory, University Hospital of Wales, Cardiff CF14 4XW, UK

4. School of Medicine, Cardiff University, Cardiff CF14 4XW, UK

5. All Wales Genetics Laboratory, University Hospital of Wales, Cardiff CF14 4XW, UK

Abstract

The collection of dried blood spots (DBS) facilitates newborn screening for a variety of rare, but very serious conditions in healthcare systems around the world. Sub-punches of varying sizes (1.5–6 mm) can be taken from DBS specimens to use as inputs for a range of biochemical assays. Advances in DNA sequencing workflows allow whole-genome sequencing (WGS) libraries to be generated directly from inputs such as peripheral blood, saliva, and DBS. We compared WGS metrics obtained from libraries generated directly from DBS to those generated from DNA extracted from peripheral blood, the standard input for this type of assay. We explored the flexibility of DBS as an input for WGS by altering the punch number and size as inputs to the assay. We showed that WGS libraries can be successfully generated from a variety of DBS inputs, including a single 3 mm or 6 mm diameter punch, with equivalent data quality observed across a number of key metrics of importance in the detection of gene variants. We observed no difference in the performance of DBS and peripheral-blood-extracted DNA in the detection of likely pathogenic gene variants in samples taken from individuals with cystic fibrosis or phenylketonuria. WGS can be performed directly from DBS and is a powerful method for the rapid discovery of clinically relevant, disease-causing gene variants.

Publisher

MDPI AG

Subject

Obstetrics and Gynecology,Immunology and Microbiology (miscellaneous),Pediatrics, Perinatology and Child Health

Reference52 articles.

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3. CFTR variant testing: A technical standard of the American College of Medical Genetics and Genomics (ACMG);Deignan;Anesth. Analg.,2020

4. The 100,000 Genomes Project Pilot Investigators (2021). 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care—Preliminary Report. N. Engl. J. Med., 385, 1868–1880.

5. Copy-number variants in clinical genome sequencing: Deployment and interpretation for rare and undiagnosed disease;Gross;Anesth. Analg.,2018

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