Details

Autor(en) / Beteiligte

• Miller, Danny E.
• Sulovari, Arvis
• Wang, Tianyun
• Loucks, Hailey
• Hoekzema, Kendra
• Munson, Katherine M.
• Lewis, Alexandra P.
• Fuerte, Edith P. Almanza
• Paschal, Catherine R.
• Walsh, Tom
• Thies, Jenny
• Bennett, James T.
• Glass, Ian
• Dipple, Katrina M.
• Patterson, Karynne
• Bonkowski, Emily S.
• Nelson, Zoe
• Squire, Audrey
• Sikes, Megan
• Beckman, Erika
• Bennett, Robin L.
• Earl, Dawn
• Lee, Winston
• Allikmets, Rando
• Perlman, Seth J.
• Chow, Penny
• Hing, Anne V.
• Wenger, Tara L.
• Adam, Margaret P.
• Sun, Angela
• Lam, Christina
• Chang, Irene
• Zou, Xue
• Austin, Stephanie L.
• Huggins, Erin
• Safi, Alexias
• Iyengar, Apoorva K.
• Reddy, Timothy E.
• Majoros, William H.
• Allen, Andrew S.
• Crawford, Gregory E.
• Kishnani, Priya S.
• King, Mary-Claire
• Cherry, Tim
• Chong, Jessica X.
• Bamshad, Michael J.
• Nickerson, Deborah A.
• Mefford, Heather C.
• Doherty, Dan
• Eichler, Evan E.

Titel

Targeted long-read sequencing identifies missing disease-causing variation

Ist Teil von

• American journal of human genetics, 2021-08, Vol.108 (8), p.1436-1449

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations—including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences—identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.