Details on Vardict, a new variant caller, have been published recently in Nucleic Acids Research by authors, Zhongwu Lai and Jonathan Dry, among others from AstraZeneca . The current version of the Bina Read Alignment Variant Calling and Expression software module for secondary analysis includes Vardict, along with five other tools, for calling SNVs or indels from tumor-normal pairs. As the article demonstrates, VarDict has multiple strengths that extend our capabilities in variant calling beyond what was available before its release. Notably, the algorithm is particularly good at detecting indels. It also handles ultra-deep sequenced samples, which have become more common of late, and supports variant calling in tumor-only samples (in addition to tumor-vs-normal calling).
Topics: DREAM Challenge Results, Somatic Mutation Detection, Tumor-Normal, Webinar, Bina RAVE, SomaticSeq, AstraZeneca, Sequencing, VarScan, JointSNVMix, SomaticIndelDetector, VarDict, MuTect, SomaticSniper
In the previous series of posts, I’ve highlighted the clinical value gained from the first molecular diagnosis of a disease (part 1) and the increasing value as more cases come to light (part 2, part 3). But parents of rare disease sufferers have also found great emotional value in discovering their child, a rare disease sufferer, is not alone.
The recurring theme for many rare disease sufferers and their families in the past has been one of a diagnostic odyssey. It’s difficult to imagine the parents’ anguish upon discovering their baby’s potentially severe condition, and then add to that the continual testing, a multitude of referrals from one specialist to the next, mounting medical bills, and a string of changing diagnoses each with their requisite treatment. One can only have deep empathy and admiration for what the family and the affected child endure, and the sacrifices they make.
In the previous post, I shared the riveting case of Bertrand Might, as the first known sufferer from a disease due to mutations in the NGLY1 gene, and how his father’s blog helped a researcher at Baylor, Matthew Bainbridge, realize that NGLY1 mutations were giving rise to his patient’s condition as well [1,2].
First you have to get to N-of-one
In the New Yorker article, “One of a Kind: What do you do if your child has a condition that is new to science?”, Seth Mnookin chronicles the life of the Mights family whose first son, Bertrand, was born in 2007 with a condition that evaded diagnosis until he was tested with clinical exome sequencing in 2012. Bertrand suffered from a disorder that left him with limited mobility, seizures and an inability to speak, among many other symptoms. The article describes the family’s odyssey - diagnostic odyssey and beyond - as a sufferer of a rare disease. At initial diagnosis, Bertrand appeared to be the first known individual whose disease was due to a mutation in the NGLY1 gene that codes for a de-glycosylation enzyme, resulting in barely detectable levels of the protein.
When I listened to a series of talks from those running clinical exome labs at the Next Generation Diagnostics Summit last year, one of my takeaways was that the information required to identify the causal variant among multiple candidate variants was sometimes fortuitously discovered. Avni Santani of the Children’s Hospital of Philadelphia spoke about how in one patient’s case, the causative gene was identified by a Google search linking to a Facebook page that had mentioned the gene, several search pages later. It turns out the father of another patient some distance away had posted the gene name likely to underlie his child’s rare disease, asking if anyone could help illuminate what this might mean. These two patients happened to have very similar phenotypes and thus, Santani’s patient turned out to have a more definitive exome interpretation as a consequence.
At last week’s Molecular Medicine Tri-Conference, Birgit Funke, Director of Clinical Research and Development at the Laboratory for Molecular Medicine and Lab Director at Partners HealthCare, presented in the session “Can Exomes Replace Targeted Panels? Balancing Cost with Results and Regulatory Requirements”. Given her intriguing talk title, “Using Exome Sequencing as a Universal Assay to Streamline Assay Development and Laboratory Operations”, I sat down with the goal of hearing about how exomes may be at the point to replace disease-focused panels. Certainly, one can imagine how doing so could simplify the clinical lab workflow by converging from many tests to a single one.
In the previous blog post, we shared how Bina’s informatics solutions are enabling growing sizes of genomic studies at CIDR. In this post, we will share on Kristine Wylie's presentation about enhanced virome sequencing using targeted sequence capture and on Dan Burgess's introduction of Heat-Seq.
The Roche “Assembling the Puzzle” Workshop featured three amazing speakers from academia and industry: Kim Doheny, Director of the Center for Inherited Disease Research (CIDR) from Johns Hopkins, Kristine Wylie, Professor of Pediatrics from Washington University, as well as the Director of Development at Nimblegen, Dan Burgess. Each speaker explained how various Roche Sequencing solutions are being used to advance studies spanning metagenomic viral profiling to human whole genome analysis.
On December 15 of last year, the FDA launched the precisionFDA portal which was developed as part of the Precision Medicine Initiative introduced by President Obama. This new portal was designed as a means to facilitate efforts to measure the performance of methods for variant calling and sequence analysis and move the community at large towards best practises in benchmarking and validation. To this end, the portal also allows for open exchange of results.