Next Generation Sequencing of Prenatal Structural Chromosomal Rearrangements Using Large-Insert Libraries.

Precise tests for genomic structural variation (SV) are essential for accurate diagnosis of prenatal genome abnormalities. The two most ubiquitous traditional methods for prenatal SV assessment, karyotyping and chromosomal microarrays, do not provide sufficient resolution for some clinically actionable SVs. Standard whole-genome sequencing (WGS) overcomes shortcomings of traditional techniques by providing base-pair resolution of the entire accessible genome.

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression.

Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.

Background: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies.

Results: We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV.