Presenters from Boston Children’s Hospital and Iceland’s deCODE genetics detailed the impact of sequence-based diagnosis of rare disease at WuXi NextCODE’s “Genomes for Breakfast” series at ASHG17.

My last post described work on rare diseases at Children’s Hospital of Fudan University (CHFU) in China, but at our recent “Genomes for Breakfast” series at ASHG17, we also heard about the impact of sequence-based diagnosis of rare disease from colleagues in Boston and Iceland.

From our longstanding partners at Boston Children’s Hospital (BCH), we heard a detailed discussion of how sequencing hundreds of people across numerous families, and the analysis of all that data together, was accelerating our understanding of one disease: nemaline myopathy. That was presented by Alan Beggs of BCH’s Division of Genetics and Genomics, and the Manton Center for Orphan Disease Research at BCH/Harvard Medical School.

A myopathy is a disorder affecting the skeletal muscles. Typical symptoms of congenital myopathies include early onset of hypotonia and weakness, which reflect distinctive pathologic changes in the muscle fibers. There are multiple subtypes of myopathy. Nemaline myopathy is the most common subtype. It can cause painful contortions (arthrogrypothis), make patients dependent on ventilators and wheelchairs or, in less acute forms, lead to mild weakness that can still impair mobility.

One of the biggest challenges in understanding these myopathies is that they are heterogeneous in every way—clinically, pathologically, and genetically. There are multiple genes associated with different subtypes, and they are sometimes shared but can also be completely distinct. Scientists have also found multiple patterns of inheritance even for a single gene.

To try to shed light on this genetic puzzle, Beggs and colleagues have been looking in detail at the particular mutations found in certain patients and mapping those against their symptoms and inheritance patterns. Recently, the researchers sequenced 857 patients with several subtypes, including just over 300 with nemaline myopathy. The BCH researchers are using a variety of sequencing approaches, including exome analysis, RNA sequencing, and whole-genome sequencing (WGS). This is necessary, they have found, because there are unusual variants that are difficult to identify with traditional tools.

Using this array of sequencing technologies and WuXi NextCODE’s clinical interpretation and case-control research tools, they were able to identify specific genetic variants that have already been associated with certain subtypes, identify new variants, and start to predict the clinical impact of each mutation or constellation of mutations. These tools are able to instantly draw upon a wealth of data from BCH, WuXi NextCODE’s knowledge base, and public databases.

The picture that emerges is complex: a large set of variants that sometimes overlap across multiple subtypes, but sometimes are just strongly associated with a single subtype. The NEB gene is of particular interest because it is so strongly associated with nemaline myopathy and quite a bit is known about its biology. Based on these studies, Beggs and his colleagues have also suggested a more accurate approach to diagnosing nemaline myopathy. All of these are steps that benefit patients and their care, and they provide the first step toward developing new and more effective ways of treating these conditions.

The third country represented at our second breakfast was Iceland. Patrick Sulem, who leads the clinical team at deCODE genetics in Reykjavik, presented. Like our collaborators in Shanghai and Boston, but armed with a truly unique set of resources and expertise, the deCODE scientists have made significant strides in better diagnosing rare diseases in children.

The deCODE database is unique in many ways and powered to uncover rare disease-causing variants. It includes the directly sequenced whole genomes of nearly 50,000 Icelanders and 10,000 others; imputed whole genome data on some 400,000 Icelanders; and SNP data from nearly a million people around the world. This gives deCODE allelic frequency data of unrivaled detail. As we have shown, this data can be helpful in diagnosing disease around the world—but when used in Iceland itself, it can point straight to pathogenic mutations and provide a map to wherever they lie in the population.

These strengths are based on some advantages of the population approach, some that others would like to replicate, others that are tough to match. Iceland’s population participates in genetics studies at a higher rate than that of any other country; Iceland has a long, strong tradition of preserving ancestry records and so has a nearly complete national genealogy for the modern era; and a national health system with a centralized record system. These ingredients have given deCODE the right data to find important variants in diseases that have baffled others. (For more details, read my post on Kari Stefansson’s headlining talk for our breakfast series.)

Based on deCODE’s work, it is now evident that whole-genome sequencing (WGS) can greatly improve diagnosis and clinical management of infants and children with hard-to-diagnose diseases. Like their peers at BCH and CHFU, researchers in Iceland have been able to use genomic screenings not just for better diagnoses—giving parents at least the comfort of knowing what’s wrong—but also, in some cases, they have been able to offer better guidance for the children’s treatment.

One such case was the result of the early application of our technology, before NextCODE had spun out of deCODE. It involved two sisters who had undergone a diagnostic odyssey of several years. With whole-genome sequence data from them and their parents, and with the ability to filter allelic frequency data in the context of different modes of inheritance, we were able to identify the culprit variant—a previously unknown variant causing Brown Vialetto Van Laere syndrome—in a matter of minutes. Because the variant was disrupting a riboflavin transporter gene, the diagnosis immediately suggested riboflavin therapy, a course of treatment that halted the progression of their disease.

Finally, it is important to note that the identification of rare disease variants is a promising avenue for feeding drug discovery—not just for the rare conditions themselves, but also potentially for much more common conditions, of which rare diseases can be extreme versions. Solving rare disease is a challenge for us all—indeed, it is a common challenge in the truest sense. The more diagnostics we do, the bigger our databases all over the world, and with the informatics and tools to mine all this data, the more benefits we can deliver to people around the world.