It’s February 28th, International Rare Disease Day, an occasion I usually try to get a post up here on KidsGenomics. Rare diseases are individually rare — in Europe they’re defined as disorders affecting fewer than 5 in 10,000 people (1:2000) and in the US fewer than 200,000 Americans (effectively 1:1700) — so they’re sometimes perceived as something only affecting a tiny fraction of the population. However, as anyone working in this space knows, rare diseases affect millions of people around the world for three key reasons:
- There are tens of thousands of different rare diseases. Among the 300+ patients enrolled in our long-running study, most diagnoses are unique. In rare occasions, we’ve found 3-4 local patients who have the same molecular cause at the gene level.
- A rare disease affects more than just the proband. Usually it’s a burden shared by the entire family — parents, siblings, and extended family come to doctor visits, enroll in studies, and are subject to the implications of a genetic diagnosis.
- As conditions that often present early in life and can affect multiple organ systems, they have an outsized impact on healthcare systems. Diagnoses can take years. The costs of care and management can last decades and span generations.
We made considerable progress this past year on several fronts related to research and patient care. Yet I would be remiss not to point out that rare disease research and clinical care, like many areas of healthcare, are currently facing existential threats.
Research and Gene Discovery in Rare Disease
It was a good year for publications. Several of our long-running GeneMatcher collaborations came to fruition, including:
- KCNB2, in which monoallelic variants cause a neurodevelopmental disorder associated with ion channel dysregulation
- MARK2, in which variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling
- DDX17, a new gene implicated in an autosomal dominant neurodevelopmental disorder caused by de novo mutations.
- EEF1A2, a known gene for epileptic encephalopathy for which we significantly expanded the phenotypic and genotypic spectrum
We had the satisfaction of ending the diagnostic odyssey for a family with autosomal dominant combined variable immunodeficiency. It turned out the cause of their disease was a novel variant in IKZF1, the IKAROS gene, which eluded detection via exome sequencing due to coverage issues associated with an early kit.
We also continued to leverage (and justify) the power of long-read sequencing for rare diseases associated with genomic structural variation. The costs, technical capabilities, and analysis infrastructures for PacBio sequencing continue to improve (thank you, REVIO)… and the more we use it, the more we’re finding that many “simple” copy number variants are complex structural rearrangements such as inverted duplications.
Our institution, like many others, shifted from exome sequencing to genome sequencing as the comprehensive test for patients with suspected genetic diseases. It’s no secret that my colleagues and I have long favored genome sequencing over exome. The long-awaited shift to clinical genome does have costs, but offers tremendous advantages in the long run in terms of diagnosis,
Patient Family Organizations for Rare Diseases Are Under-appreciated
I had the opportunity to engage more with a couple of these organizations this year after identifying new patient families: The CNKS2A1 Foundation, which was formed by families dealing with Okur-Chung Neurodevelopmental Syndrome (OCNDS) associated with variants in CSNK2A1, and Helping Hand for GAND, which is for patients with GATAD2B-associated Neurodevelopmental Syndrome.
By random chance, the hotel in which I was staying during the ASHG 2024 annual meeting was hosting an annual event for yet another patient organization. It offered me a glimpse — from passing conversations in the elevator or the breakfast room — of how kind and tight-knit these communities are.
As researchers, we know that rare disease patient/family organizations exist and we’re aware of their value, especially to families of affected patients. They’re often small organizations, but scrappy ones, and I hope to find more ways to engage and support them more.
The Dire Threats to Research in the US and Elsewhere
In spite of the progress and promise over the past year, it’s necessary to acknowledge that not everything is going well. Arguably the largest and most important source of research funding in the world has been hobbled by the incoming administration. The NIH is hardly the only government body being upended, and a great deal of uncertainty remains, but there are two realities of the current landscape that we should acknowledge.
- NIH grant funding, at the moment, is completely halted. Even for awarded grants, no money is going out to anyone. Most study section meetings and advisory council meetings scheduled in 2025 have been canceled. Not rescheduled. Canceled. This means that after the purse opens again — if it opens again — we’ve lost nearly an entire funding cycle. For researchers who require grant support to exist, that will have devastating consequences. So will the mass layoffs. When the dust settles, a lot of the people who were administering grant programs will be gone.
- Indirect funding is under intense scrutiny and may be cut dramatically. “Indirects” or “Overhead” are, in the simplest terms, money that the NIH gives an institution where investigators have won grants to help those institutions operate. That’s because the direct costs of a grant can only be spent on certain things like staff salary, reagents, and some equipment. You can’t use direct funds for things like utility bills, administrative staff, building maintenance, security… it’s a long list. The only reason that research happens anywhere is that the NIH pays indirect costs to the organization. At most places, for every dollar of grant funding awarded, the institution gets an additional $0.40 to $0.60 to keep the lights running. The federal government announced that this will be cut to $0.15 per dollar of funding. That’s a major cut. Institutions like ours will lose tens of millions.
This is hardly the only existential threat faced by the healthcare/research community, but it’s a pretty big one. We will carry on as best we can, of course. But these are dark times indeed.
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