February 29, 2016  |  General

On Rare Disease Day, celebrating the contributions of genomics

Today we are celebrating Rare Disease Day with like-minded folks all over the world. The tribute kicked off in 2008 and has gathered so much momentum that people in more than 80 countries are expected to participate in 2016. Each disease is rare — affecting fewer than 1 in 1,500 people — but because there are so many of these diseases, together they affect millions of people globally.

Here at PacBio, many of our team members have their own stories about dealing with rare disease, and we imagine the same is true of our blog readers. We’re so proud that leading scientists have already begun using SMRT Sequencing to make important new DNA and RNA discoveries about the genetics and disease mechanisms of rare diseases. In the future, we anticipate even more of these studies will lead to novel breakthroughs as scientists expand their use of PacBio sequencing for human disease studies. Together, we can have a real impact in helping families struggling with these diseases.

Here are some examples of how researchers have shed light on rare diseases with SMRT Sequencing:
Baylor’s Jim Lupski, who studies and has been diagnosed with Charcot-Marie-Tooth neuropathy, recently spoke about a de novo PacBio assembly of his genome that found much more structural variation — especially copy number changes — than previous assemblies from short-read data. He also described how long reads are able to better resolve and characterize break points associated with these disease-causing structural variants, and also resolve sequence context to provide base-level resolution of specific genotypes.

In a separate presentation, Richard Gibbs from Baylor College of Medicine noted that just 25% of Mendelian disorders have been solved with short-read sequence data, and suggested that the success rate may be limited by the inability of these platforms to detect structural variation, repeat regions, and complex events. With SMRT Sequencing and structural variation analysis algorithms created at his genome center, scientists may be able to uncover the genetic basis of many more Mendelian disorders using low-coverage, long-read PacBio sequencing.

Paul Hagerman from the University of California, Davis, led the first team in the world to completely sequence a fully expanded pathogenic ‘CGG repeat allele’ in the FMR1 gene on the X chromosome that is associated with Fragile X Syndrome. Previously thought to be “unsequenceable,” PacBio sequencing of repeat expansions in the FMR1 gene is shedding new light on pathogenic variants and interruptions that are meaningful for screening and carrier counseling, and that may lead to improved diagnostic and intervention strategies for families affected by Fragile X syndrome.

In a related project, follow-up work from Flora Tassone and other UC Davis researchers applied the Iso-Seq method to characterize alternative splicing in the FMR1 gene for a different disorder called Fragile X-associated tremor/ataxia syndrome (FXTAS). They found differential expression for certain gene isoforms suggesting a functional relevance for these in the pathology of FMR1-associated disorders.

Scientists in North Carolina generated the first high-quality sequence of MUC5AC, a gene that has been implicated in a range of diseases, including cystic fibrosis. The gene had long been represented as a gap in the human reference genome because of its complex and highly repetitive central exon. Characterization of the MUC5AC gene and the sequence variation in the central exon will facilitate genetic and functional studies for this critical airway mucin.

In a recent talk at AGBT, Bobby Sebra from the Icahn School of Medicine presented results from the recent targeted PacBio sequencing of the C9orf72 loci, which contains a GGGGCC repeat expansion now known to cause familial ALS (also known as Lou Gherig’s Disease). He presented sequencing data from both the PacBio RS II platform and the new Sequel System, showing the ability to fully characterize the sequence of this locus and provide novel insights into the genetics underlying this debilitating disease.

Tetsuo Ashizawa and Karen McFarland from the University of Florida are making progress understanding the genetics of spinocerebellar ataxia type 10 (SCA10). In a recently published study, they describe sequencing through a pentanucleotide repeat allele known to cause this disorder, and characterizing various repeat interruption motifs associated with different SCA10 clinical phenotypes.

Shinichi Morishita’s lab at the University of Tokyo has described similar methods for characterizing tandem repeats associated with the SCA31 brain disease using a hybrid long- and short-read approach.

At Stanford University, Ayal Hendel is working in collaboration with John Day and the Myotonic Dystrophy Foundation to study the CTG/CAG repeat tracts that represent the genetic basis for myotonic dystrophy type 1 (DM1), and explore the cellular and molecular pathological mechanisms involved in DM — including aberrant alternative splicing.

We’d like to congratulate these scientists, along with all the others around the world who are working hard to make a difference in the lives of people burdened by rare disease. Whether you’re using our technology or any other, we thank you and wish you all the best!

PacBio is proud to be an official partner of Rare Disease Day. Get involved with global efforts or US-based initiatives to honor those dealing with rare diseases.

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