Detection of Large Structural Variants Causing Inherited Retinal Diseases.

Current application of next-generation sequencing (NGS) leads to detection of the underlying disease-causing gene and mutation or mutations in from 60% to 85% of patients with inherited retinal diseases (IRDs), depending on the methods used, disease type, and population tested. In a cohort of 320 families with autosomal dominant retinitis pigmentosa (adRP), we have detected the mutation in 82% of cases using a variety of methods, leaving more than 50 families with "elusive" disease genotypes. All of the remaining families have been screened for mutations in known IRD genes using retinal-targeted-capture NGS, and most have been tested by whole-exome NGS.

Adjusting family relatedness in data-driven burden test of rare variants.

Family data represent a rich resource for detecting association between rare variants (RVs) and human traits. However, most RV association analysis methods developed in recent years are data-driven burden tests which can adaptively learn weights from data but require permutation to evaluate significance, thus are not readily applicable to family data, because random permutation will destroy family structure. Direct application of these methods to family data may result in a significant inflation of false positives.

The functional spectrum of low-frequency coding variation.

Background: Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency.

Results: The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples.

DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes.