SMRT Leiden 2019 Day 2: Evolving Towards Precision Medicine with Longer, Accurate Reads
By: Liz T
Tags: Genetics, Biotechnology, Dna, Science, Dna Sequencing

Euan Ashley (@euanashley, Stanford) began the second day of SMRT Leiden with a keynote presentation on precision medicine.

What is the definition of precision medicine?

Before defining precision medicine (or personalized medicine), the more important question to ask should be: why is precision medicine needed?

The answer could be found in Ashley’s disclosure of personal interest: “I want to help patients”.

Or, if one recalls the next sentence in President Obama’s State of the Union address, “To give all of us access to the personalized information we need to keep ourselves and our families healthier.”

Delivery of such information must not only be accurate, but also timely. One such case was the diagnosis of a newborn suffering from long QT syndrome, a condition that causes irregular heartbeats, where whole genome sequencing confirmed a pathogenic variant in KCNH2 gene at 10 days post birth. At that time, standard genetic testing would have taken 4 to 16 weeks.

And for many, though urgent delivery of information is not a matter of life or death, the eventual diagnosis means the world to them. The Undiagnosed Disease Network (UDN) was established in 2014 to solve rare, previously undiagnosed diseases. Within a 20-month period, they delivered diagnoses for 132 out of 382 cases, a 35% solve rate. More importantly, 79% of the solved cases had actionability; 1/3 of which led to changes in therapy. Finally, there’s cost! The average cost of patients who received a diagnosis before coming to UDN was ~$300,000, whereas the UDN diagnosis cost was only ~$18,000, or 6% of the previous cost. The value of an accurate genomic diagnosis was not just medical and emotional, but also financial.

So that’s the good news. But the other side of the 35% solve rate is that 2/3 of the patients still have no answer for their illness.

What are we missing?

Precision medicine, Ashely defined, is the treatment or prevention of diseases by more precise measurement. But the human genome is complex. It is filled with repeat sequences, paralogous genes, and mosaicism. For many of the repeat diseases — Fragile X, myotonic dystrophy, Huntington’s, just to name a few — “short reads just are not able to characterize these highly polymorphic regions,” Ashley said. Computationally, these regions also present challenges.

Keynote by Euan Ashley on the progression of precision medicine. Sketch provided by @ATJCagan.

“Precision medicine has to be accurate medicine. If we are not measuring the whole genome, we will fail to find the genetic causes for our patient’s diseases.”

The solution? Better algorithms, graph reference genomes, and long reads.

Ashley presented the instance where PacBio sequencing solved the case of a patient with recurrent myxomas. It was suspected that he had Carney complex, yet prior genetic testing including WES and WGS failed to identify the causal variant. Using low-fold sequencing on the PacBio Sequel System, they identified — using just 4 long reads — a heterozygous 2kb deletion in the PRKAR1A gene. Sequencing of the parents confirmed this to be a de novo variant.

Ashely then shared another case where a causal variant was identified at the FAM177A1 gene, and they are still working to link the variant and the disease phenotype.

For some of the unsolved diseases, RNA may play a role as well. Ashley pointed to a recent project of looking at the MYBPC3 isoform diversity using targeted Iso-Seq (paper to appear in Circulation: Genomic and Precision Medicine soon) where PacBio long reads enabled accurate haplotyping at the isoform level.

Ashley is optimistic that with improved sequencing technology, better reference genomes, and faster algorithms, we will be able to solve more of the rare diseases.