Scientists recently announced the first fully complete human genome. It reveals previously hard-to-sequence regions that were missing in the first essentially complete human genome sequenced nearly two decades back. Between the two milestones, genome sequencing technologies have become faster, cheaper, and more reliable by orders of magnitude. This is catalyzing a range of clinical applications.

Genome sequencing has enabled scientists, for instance, to map variations in gene sequences to differences in susceptibility to diseases, allowing clinicians to personalize treatment to each individual. Scientists have discovered genomic markers of multiple cancers that are far more reliable than mammograms or microscopic examinations. And the technology also provides parents opting for in-vitro fertilization with genetic information on fertilized embryos to help them make more informed decisions.

Beyond these applications, sequencing genomes is advancing research into a relatively unexplored frontier: rare diseases. While the exact rate varies by the country—ranging anywhere from 1 in 1,000 to 1 in 100,000—a rare disease, by definition, affects a minute fraction of the general population.

However, if we count all the people with both known and unknown rare diseases, that adds up to a mind-boggling scale. One estimate published in the European Journal of Human Genetics put the number of people affected worldwide by rare diseases at over 300 million. Because of a lack of diagnosis and treatment options, many of these people suffer in silence.

Improving diagnosis of rare diseases

To understand how genomic studies contribute to our understanding of rare diseases, I spoke to Dr. Claudia Gonzaga-Jauregui, a principal investigator at the International Laboratory for Human Genome Research (LIIGH) at the National Autonomous University of Mexico (UNAM). Her work looks into the molecular causes of rare genetic disorders in patients with undiagnosed conditions.

Dr. Gonzaga-Jauregui told me that there are many people that may seem “normal” in the general population, but actually carry rare variants associated with genetic disorders in their genomes. “So many of them have undiagnosed genetic conditions that are generally misdiagnosed with more common diseases like diabetes or high cholesterol when they actually have genetic conditions that put them at higher risk of developing these disorders,” she explained.

For a patient, having no diagnosis for their condition can be mentally and emotionally straining. Referred to as the diagnostic odyssey in rare disease circles, finding the right diagnosis is an arduous journey filled with uncertainty. In a study that documented experiences of rare disease patients who received a genomic diagnosis, relief was a common emotion shared by patients and their close relatives. One parent whose child was diagnosed with a rare disorder, for instance, said that she “felt guilt— it was like horrendous, actually. So that lifted.”

In recent years, genomic medicine has made it possible for many such patients to seek accurate diagnoses. To further improve the accuracy of diagnosis, researchers are increasingly integrating genome sequencing data with phenotyping and other omics technologies such as proteomics and transcriptomics. While sequencing only tells which genes are present, these technologies paint a comprehensive picture of which genes are expressed, made into proteins, and what they do in the cells.

With an accurate diagnosis at hand, rare disease patients are empowered to enroll in clinical trials for their conditions or receive treatment, if any exists, or get their family members tested. This has the potential to prevent innumerable avoidable deaths and improve the quality of life of millions of patients.

Genomics provides benefits for the treatment of well-characterized rare diseases as well. Protein-coding parts of the genes comprise just 1% of the total genome. Exome sequencing lowers cost considerably by focusing on solely these regions as a proxy for sequencing all genes. It also improves coverage of the regions where genetic determinants for many rare diseases with known mechanisms are. And like for most diseases with a genomic diagnosis, it brings down the time for a diagnosis from weeks, or even years, to days. 

Large-scale initiatives bridging the gaps

Just by being able to sequence more genomes, in little over a decade, the number of known rare diseases has risen from nearly 3,000 to more than 7,000. Our understanding of rare diseases will grow exponentially as we sequence even more genomes over the next decade.

The 100,000 Genomes Project, undertaken by the National Health Services in the UK, demonstrated how sequencing large numbers of genomes can provide novel insights into rare diseases. For a pilot study, the researchers looked into the genome sequences of 4,600 participants from 2,183 families. Since most rare diseases are genetic, family genome sequencing vastly improves the confidence in a diagnosis.

The probands (jargon for the first person in a family to be sequenced) were people who were suspected of having a rare disease and had not received a genomic diagnosis. In a preliminary report published last year, researchers noted that 1 in every 4 of these individuals had a rare disease. The study showed that combining genome sequences with other computational approaches improves diagnostic yield, even for cases where genomic sequences alone wouldn’t have sufficed. Among other insights, it brought to light 579 previously unknown disease-gene associations.

Large-scale, international initiatives are striving to make access to genome sequencing more equitable. This would help rare diseases patients living in developing countries or countries with high economic disparity who face the double whammy of a lack of diagnosis for their conditions and poor healthcare systems. 

The International Rare Diseases Research Consortium (IRDiRC) identified filling this gap as a major goal in its future of rare diseases report. It suggested a globally coordinated diagnostic and research pipeline to track all individuals with as-of-yet undiagnosable rare diseases. To this end, researchers manage and contribute to databases like Orphanet and Online Mendelian Inheritance in Man (OMIM). They also collaborate with international programs like Undiagnosed Diseases Network International (UDNI) as well as regional programs.

“Unfortunately, patients that happen to be born or live in countries that are not Europe or the US or Canada or the UK have little access to genome sequencing technologies and can still spend their whole life without a diagnosis,” Dr. Gonzaga-Jauregui told me. “I think that’s unacceptable and the international community needs to make an effort to really make it available to everyone no matter where they are born or live.”

She added that “if anyone has a disorder that’s suspected to be genetic, they should have access to genomic testing so they have an answer.”

Sequencing more and diverse genomes

The cost of human genomic sequencing continues to fall rapidly due to advances in high-throughput technologies and the ability to sequence longer DNA sequences. Consequently, their use in routine clinical practice is on the rise. As we sequence more and more genomes, we will have more coverage for each base pair in the human genome. Over time, this will reveal more cases of what are called ultra-rare diseases.

These are diseases for which “there might be one or two patients in the whole world. If we don’t get to those patients, we are not going to identify those diseases,” Dr. Gonzaga-Jauregui noted. The odds of catching such diseases are literally at the scale of one in a billion. Advancing research into these requires collaboration and communication between rare disease researchers across the globe.

“Say I found a patient in Mexico with a new mutation that hasn’t been reported. We put it in these systems that had been developed to share data among the community. And then someone else finds another mutation in the same gene in another patient in, say, Pakistan.  That’s what we call gene matching,” Dr. Gonzaga-Jauregui elaborated.

If the researchers find two or three such patients that share similar phenotypes and the same mutations in genes suspected to be causing the disorder, it is a hint that the two may be linked. However, finding a novel mutation isn’t by itself sufficient and requires further clinical work such as functional studies of the gene in cell lines or mice.

Sequencing more genomes will and should include genomes of underrepresented populations, particularly people of color and women. An overwhelmingly high number of genomes sequenced to date are of people with European ancestry. As a result, our understanding of the genetic makeup of the human genome is closer to that of a White person’s genome and doesn’t adequately represent everyone else.

It is now well documented how BMI, a metric designed for European body standards, misclassified people of color and those with certain conditions. Replicating insights derived from mainly White genome datasets for the treatment of other demographics could also similarly lead to incorrect or missing diagnoses.

Dr. Gonzaga-Jauregui stressed that we are missing out on “variants, even in known genes, in other populations that haven’t been characterized or reported and that are causing genetic disorders.” 

While all humans share nearly 99.1% of DNA, the other 0.1% plays an important role in shaping who we are, including what diseases affect us. “Because of their different demographic histories, different populations will have different prevalences of these diseases. They will also have other alleles with higher frequencies.”

We need to include this diversity of genomic information in health policy or early prevention measures for specific disorders to ensure genomic medicine benefits all populations. For diagnosis and management of rare diseases, nowadays lack of equity is a greater challenge than genomic technologies.

Fortunately for all of us, and particularly for rare disease patients, researchers like Dr. Gonzaga-Jauregui and projects like 100,000 Genomes are advocating for a future where the benefits of human genome sequencing will be accessible to everyone. The current work on rare disease diagnosis will pave the way for a better understanding of human biology, the creation of therapies for rare diseases, better drug development for rare and common diseases, and the widespread adoption of precision medicine.