Author:
Hiatt Susan M.,Lawlor James M.J.,Handley Lori H.,Ramaker Ryne C.,Rogers Brianne B.,Partridge E. Christopher,Boston Lori Beth,Williams Melissa,Plott Christopher B.,Jenkins Jerry,Gray David E.,Holt James M.,Bowling Kevin M.,Bebin E. Martina,Grimwood Jane,Schmutz Jeremy,Cooper Gregory M.
Abstract
AbstractPurposeExome and genome sequencing have proven to be effective tools for the diagnosis of neurodevelopmental disorders (NDDs), but large fractions of NDDs cannot be attributed to currently detectable genetic variation. This is likely, at least in part, a result of the fact that many genetic variants are difficult or impossible to detect through typical short-read sequencing approaches.MethodsHere, we describe a genomic analysis using Pacific Biosciences circular consensus sequencing (CCS) reads, which are both long (>10 kb) and accurate (>99% bp accuracy). We used CCS on six proband-parent trios with NDDs that were unexplained despite extensive testing, including genome sequencing with short reads.ResultsWe identified variants and created de novo assemblies in each trio, with global metrics indicating these data sets are more accurate and comprehensive than those provided by short-read data. In one proband, we identified a likely pathogenic (LP), de novo L1-mediated insertion in CDKL5 that results in duplication of exon 3, leading to a frameshift. In a second proband, we identified multiple large de novo structural variants, including insertion-translocations affecting DGKB and MLLT3, which we show disrupt MLLT3 transcript levels. We consider this extensive structural variation likely pathogenic.ConclusionThe breadth and quality of variant detection, coupled to finding variants of clinical and research interest in two of six probands with unexplained NDDs strongly support the value of long-read genome sequencing for understanding rare disease.
Publisher
Cold Spring Harbor Laboratory
Cited by
5 articles.
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