RT Journal Article
SR Electronic
T1 Long-read whole genome sequencing identifies causal structural variation in a Mendelian disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 090985
DO 10.1101/090985
A1 Jason D. Merker
A1 Aaron M. Wenger
A1 Tam Sneddon
A1 Megan Grove
A1 Daryl Waggott
A1 Sowmi Utiramerur
A1 Yanli Hou
A1 Christine C. Lambert
A1 Kevin S. Eng
A1 Luke Hickey
A1 Jonas Korlach
A1 James Ford
A1 Euan A. Ashley
YR 2016
UL http://biorxiv.org/content/early/2016/12/02/090985.abstract
AB Current clinical genomics assays primarily utilize short-read sequencing (SRS), which offers high throughput, high base accuracy, and low cost per base. SRS has, however, limited ability to evaluate tandem repeats, regions with high [GC] or [AT] content, highly polymorphic regions, highly paralogous regions, and large-scale structural variants. Long-read sequencing (LRS) has complementary strengths and offers a means to discover overlooked genetic variation in patients undiagnosed by SRS. To evaluate LRS, we selected a patient who presented with multiple neoplasia and cardiac myxomata suggestive of Carney complex for whom targeted clinical gene testing and whole genome SRS were negative. Low coverage whole genome LRS was performed on the PacBio Sequel system and structural variants were called, yielding 6,971 deletions and 6,821 insertions > 50bp. Filtering for variants that are absent in an unrelated control and that overlap a coding exon of a disease gene identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. This variant was confirmed by Sanger sequencing and was classified as pathogenic using standard criteria for the interpretation of sequence variants. This first successful application of whole genome LRS to identify a pathogenic variant suggests that LRS has significant potential to identify disease-causing structural variation. We recommend larger studies to evaluate the diagnostic yield of LRS, and the development of a comprehensive catalog of common human structural variation to support future studies.