Pilot studies of the efficacy of Genomics in diagnosing critically ill newborns have led some experts to proclaim that Genomics has its long-awaited and much-needed "killer-app." In this, I concur. In diagnosing Rare Diseases in days, rather than the traditional "diagnostic odyssey" which can typically run into the 5 to 10 year range, I believe it has another. What began as a slow but steady trickle has turned into a flowing river of news stories, on an almost daily basis: patients being diagnosed, new genetic biomarkers discovered, and new disorders identified, thus supplanting mystery ailments which, until presently, contained only symptoms.
From small independent clinics to universities, from hospitals to foundations, to large "showcase" endeavors such as the UK's 100,000 Genomes Project and the US-based Undiagnosed Diseases Network, which just this past week began recruiting patients, the sound of genome-sequencers spinning away is a sound which will, no doubt, be ramping up from a dull hum to a loud roar in the not-too-distant future.
Prevalence statistics for most Rare Diseases are based for the most part on rough estimates. What widespread use of genome-sequencing will bring to these disorders, however, is a high degree of quantification and accuracy. The Rare Disease map, in essence, stands to be comprehensively and fundamentally redrawn.
Experts have long posited that for every diagnosed Rare Disease patient, there are an average of 2 to 3 who are undiagnosed, and with lack of diagnosis, comes absence from prevalence statistics. This proved to be the case with Severed Combined Immunodeficiency ("Bubble-Baby" disorder). SCID, due to widespread use of newborn screening (19 states in the US, portions of Europe, and most recently nationally throughout Israel) is arguably the most widely studied, documented and verified of the Rare Diseases, purely in terms of prevalence. As late as the 1970s, the prevalence of SCID was estimated to be in the order of 1 in 250,000 births. That estimate was revised downward in the 1980s to approximately 1 in 100,000. In 2014 the number was further revised down to the current 1 in 58,000 live births.
Screening for SCID is not based on genomic testing. It is carried out via the Guthrie method: the newborn screening heel-prick, subsequent blood spot, and traditional genetic analysis based on well-established biomarkers. SCID prevalence however, despite being quantified by non-genomic means, is indicative of one very important concept - what occurs when reliable, large-scale, statistically-significant data for a disease is collected, collated, and analyzed.
J. Craig Venter, Genomics guru and one of the pioneers of the Human Genome Project stated at "Exponential Medicine 2014" that by the year 2020, 5 million individuals will have had their genomes sequenced. Many estimate that number could reach close to a billion in the coming two decades. Whether one chooses to stop at 2020 and gawk, or look well beyond at the mind-blowing figures, one thing is clear - the massive, unprecedented flow of genetic data will provide a rich source of information to quantify diseases, among them the rare. Herein lies a conundrum for the Rare Disease world.
Approximately 7,000 disorders currently meet the criteria for a rare designation - among them genetic disorders, chromosomal disorders, many rare cancers, and almost all pediatric cancers. That criteria varies - from the United States to Europe to individual countries with their own Rare Disease programs and methodology for establishing rarity. On average, however, a disease can be considered rare if at affects less that 1 in 2,500 individuals. Rare Diseases run the gamut of prevalence range - from 1 in tens-of-thousands to 1 in-millions to ultra-rare disorders in which only a handful of individuals globally have been diagnosed. The 7,000 Rare Diseases, however, are not spread evenly across this continuum. The largest portion - up to 20% - are fixed in the least-rare range: from 1 in 2,500 to 1 in 4,500. The significance of this is critical as we revisit the case of SCID.
If any, many, most, or all of these 20% of "least-rare" Rare Diseases - approximately 1,500 disorders in all - are found to be at least twice as common as current prevalence statistics suggest, they will no longer meet the criteria of being considered rare. With widespread use of genome-sequencing, and massive data-crunching, this is something which is likely to occur - to one degree or another. Those 2 to 3 undiagnosed cases for each individual diagnosed, alluded to earlier? Chances are high that they will be found. Not all perhaps, but at least in cohort studies which will provide the data for prevalence statistics.
Individuals diagnosed with these disorders will benefit greatly by being diagnosed. From the clarity inherent in diagnosis to early treatment intervention to data which can be used to develop treatments and cures to the building of larger cohorts of individual diseases, benefits will abound.
Many Rare Diseases however stand to lose much, in an ironic Catch-22. Orphan Drug Acts, which take various forms in the United States, Europe, and in other incarnations throughout the world, grant massive incentives (tax credits and long-term market exclusivity, to name but a few) for both pharmaceutical and biotechnological companies, as well as other institutions, to develop treatments and prospective cures for specific disorders, based upon one criteria and one criteria alone - rarity. Incentive is the methodology by which these R&D organizations are for the most part "enticed" to outlay vast sums of money to develop therapies for small patient populations - outlays which typically would result in heavy, negative return on investment. The large issue, and in my opinion, a cause for at least initial concern, is that when diseases, individually or en-masse, lose their rare designation, they stand to fall between the proverbial cracks like never before. Pharma and biotech could be forced to shun these once attractive suitors.
What will happen when statistics from widespread genome-sequencing show that Disease "XYZ," rather than having a prevalence of 1 in 3,500 individuals, has, in fact, a prevalence of "only" 1 in 1,400 individuals? Will it be banished from the Rare World altogether? Will it somehow be "grandfathered" into rarity by the powers-that-be - once rare always rare? Will rare disease criteria somehow be tweaked to accommodate changes in frequency and prevalence? Questions abound. For Rare Disease "XYZ," "GHI," "OPQ," and so on. And so on. And so on.
One thing is certain: Genomics presents a double-edged sword to the Rare community. Individuals will reap the benefits and rewards of this next-generation technology which only a few short years ago seemed the stuff of science-fiction. Diagnosis will be transformed. Medicine will become more personalized. But the Rare Disease map also stands to be redrawn in what might prove to be a tectonic shift in what it means proverbially, technically, legally, and financially to be rare.