This week we celebrate Rare Disease Day, which aims to raise awareness for rare diseases and improve the medical and research support for individuals with rare diseases and their families. I’ve worked in the rare disease research space for several years, and it does feel like the importance of these conditions is increasingly recognized. Earlier this week, U.S. Senators Sherrod Brown (D-OH) and John Barrasso (R-WY) announced the passage of their Senate resolution designating February 28, 2023 as “Rare Disease Day” in the US. When the two major political parties in our country agree on something, it’s kind of a big deal.
Our institution, like many others, hosted an event for patients, families, clinicians, and researchers who are invested in rare disease. It was a special occasion this year as we returned to in-person and celebrated the recognition of Nationwide Children’s Hospital as a Rare Disease Center of Excellence by the National Organization for Rare Disorders (NORD). The keynote speaker was Dr. Jerry Mendell, a pioneer in gene therapy, who shared some of the challenges and successes of developing viral gene therapies for devastating diseases like spinal muscular atrophy and Duchenne Muscular Dystrophy. Watching videos of his patients before and after therapy… well, it’s inspiring to say the least.
The State of Rare Disease Research in 2023
The first step to treating a patient with a rare disease is to obtain a molecular diagnosis. Because the vast majority of rare diseases have genetic origins, this is an area that has seen dramatic advances in the era of high-throughput sequencing. I listen to many scientific talks about disease genetics and gene discovery. Many of them report around ~8,000 gene-disease associations currently in the OMIM database. This week I heard that modern counts are higher, something closer to 12,000. Anecdotally, it’s obvious to those of us who work in gene discovery that at least 2-3 new disease-gene relationships are published in peer-reviewed journals per week.
For many clinical and research laboratories, the OMIM Database is the primary authority on human gene disease associations. It’s a curated resource that is free to the public and maintained by Johns Hopkins. A few months ago, I downloaded the entire database of OMIM associations and did some rudimentary analyses. At that time, OMIM contained:
- 18,077 recognized human genes
- 7,333 phenotypes mapped to a gene
- 6,473 of which are genetic disorders (versus susceptibility and quantitative trait associations)
- 5,955 of which are Mendelian disorders with an established pattern of inheritance
Inheritance of OMIM Disease Genes
As you can see from the pie chart, autosomal recessive disorders are the most prevalent category (53%), followed by autosomal dominant (35%). I imagine the gap between those two categories has been shrinking, as the majority of newly discovered genes in this era are associated with de novo mutations and thus classified as autosomal dominant. A small proportion of disorders are described as both AD and AR. Sometimes that is true. Other times, most patients in the literature are biallelic (AR), but there’s some [usually 10+ years old] published study of a patient with disease who has only one heterozygous variant in the gene. In my experience, if that patient were studied with modern approaches — whole-genome sequencing and transcriptome analysis — there’s a good chance a second variant would be identified.
X-linked inheritance patterns were lumped together for the pie chart, but most are X-linked recessive (n=216), as opposed to X-linked dominant (n=62) or unspecified X-linked inheritance (n=69). With the latter category, if you go and read about those disorders, many have only been reported in affected males and thus are likely to be X-linked recessive.
Somatic inheritance is not really a Mendelian pattern, but I included it as the 5th most common category of OMIM disease genes with >200 curated. Most of these are cancers or cancer syndromes associated with well-known genes like APC, KRAS, and PIK3CA, but there are a handful of somatic-mosaic disorders recognized. This is another category likely to grow substantially as our ability to detect disease-causing variation in relevant tissues and cell types improves.
Other inheritance patterns are recognized by OMIM but are too rare to be shown in a pie chart. These include things like digenic inheritance (n=16) and pseudo-autosomal inheritance (n=4). There are even a handful of Y-linked disorders. Frankly, I’m dubious of most associations in these categories, but once something is established in OMIM, it’s hard to go back.
Curation versus Gene Discovery
One of the major reasons OMIM is so popular is that it’s curated and updated with biomedical literature. In the genomics field, we have come to love curated resources because, generally speaking, the quality is much higher. Yet in the case of OMIM, it is clear that curation lags far behind the pace of discovery. This is unsurprising. New disease genes and expanded phenotypes are being published daily across a wide array of peer-reviewed journals. It’s hard for anyone to keep up.
Yet for patients with undiagnosed rare diseases, recent discoveries are critical. Multiple studies of the reanalysis of previously-negative exome tests have demonstrated that once 2-3 years have passed, a significant proportion (10-20%) yield diagnostic results when reanalyzed. Most of the time, it’s not pipeline improvements or sophisticated analytical tools, but due to the fact that the diagnostic finding is in a newly discovered disease gene, or a new phenotypic manifestation of a known disease gene.
Given the value of up-to-date information, how do we strike the balance? One possibility is to leverage crowdsourcing of experts in the field. This is what the Clinical Genome Resource (ClinGen) is doing with its expert panels, which interact with various working groups. I’m part of the Variant Curation Expert Panel for RPE65, a gene linked to autosomal recessive Leber Congenital Amaurosis (progressive blindness) — our duty is to help establish extremely rigorous guidelines for variant interpretation of variants in this gene. This goes a level beyond ACMG guidelines, which are fairly broad, and applies some gene/disease-specific rules for how each type of evidence could should be evaluated. The VCEP panel is complemented by a GCEP (Gene Curation Expert Panel) which reviews and establishes gene-disease associations.
Everyone on an expert panel is a volunteer, and each panel has member with complementary expertise. Since we all have a personal stake in diagnostics for this gene (or condition), we’re all invested in doing the work and reaching a useful consensus when necessary. I just took a look and wow, there are many GCEPs and VCEPs already established. That seems encouraging.
Rare Disease Genomics in 2023
There is plenty of work to do, of course. Many groups including ours will continue sequencing undiagnosed patients and connecting with other investigators via Matchmaking to help establish new disease genes. Trend-wise, I expect at least two new paradigms will emerge:
- Leveraging large-scale biobanks with genomic data to validate new disease genes and identify additional patients to better define phenotypes.
- Applying ever-more-sophisticated functional assays, including organoids, gene-edited model organisms, and other approaches, to support and explore the mechanisms of disease.
It’s going to be a busy year, but a good one, for Rare Diseases.